US20100326843A1

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Publication number: US20100326843A1
Application number: US12/495,712
Authority: US
Inventors: Songbiao Zhang; John C. Mazza; Mohammed E. Moein; Ting Chen
Original assignee: Abbott Diabetes Care Inc
Current assignee: Abbott Diabetes Care Inc
Priority date: 2009-06-30
Filing date: 2009-06-30
Publication date: 2010-12-30
Also published as: US8437827B2

Abstract

The present disclosure provides electrode structures and integrated electrode structures having one or more conductive materials coextruded with one or more dielectric materials. The disclosed electrode structures can be configured for use as analyte sensors. Also provided, are methods of making and using the electrode structures and integrated electrode structures described herein.

Description

BACKGROUND OF THE INVENTION

Electrode structures find use in a variety of applications, including, but not limited to, use in electrochemical analyte sensors. Many electrochemical analyte sensors include two or more electrodes in addition to various chemical or biochemical agents. The inclusion of multiple electrodes often requires multiple manufacturing steps which may complicate the manufacturing process and result in increased cost of production. As such, new approaches to the design and manufacture of electrode structures, which simplify the production process and/or reduce the cost of production, are of interest to the art.

SUMMARY OF THE INVENTION

The present disclosure provides electrode structures and integrated electrode structures having one or more conductive materials coextruded with one or more dielectric materials. The disclosed electrode structures can be configured for use as analyte sensors. Also provided, are methods of making and using the electrode structures and integrated electrode structures described herein. These and other objects, features and advantages of the present disclosure will become more fully apparent from the following detailed description of the embodiments, the appended claims and the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not necessarily to-scale. The dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures:

FIG. 1A andFIG. 1B show a cross-section (1A) and a perspective view (1B) of a substantially solid electrode configuration according to the present disclosure;

FIG. 2 shows a perspective view of a hollow, cylindrical extruded electrode configuration;

FIG. 3 shows a side view of the hollow, cylindrical configuration shown inFIG. 2.

FIG. 4 shows a perspective view of another embodiment of a hollow, cylindrical electrode configuration;

FIG. 5 shows a side view of the hollow, cylindrical electrode configuration shown inFIG. 4;

FIG. 6 shows a perspective view of another embodiment of a hollow, cylindrical electrode configuration;

FIG. 7 shows a side view of the hollow, cylindrical electrode configuration shown inFIG. 6;

FIG. 8 shows a perspective view of another embodiment of a hollow, cylindrical electrode configuration, including an integrated lancet;

FIG. 9 shows a second perspective view of the cylindrical electrode configuration shown inFIG. 8.

FIG. 10 shows a deconstructed view of an embodiment of an electrode structure according to the present disclosure, wherein the electrode structure includes a first extruded body and a second extruded body;

FIG. 11A shows an electrode structure formed from the first and second extruded bodies shown inFIG. 10;FIG. 11B shows a first extruded body positioned over a second extruded body prior to formation of the electrode structure inFIG. 11A;

FIG. 12 shows an embodiment of an integrated lancet and electrode structure according to the present disclosure;

FIG. 13 illustrates a fluid sample extraction and collection process using the integrated lancet and electrode structure shown inFIG. 12;

FIG. 14 shows the integrated lancet and electrode structure ofFIGS. 12 and 13 after extraction and collection of the fluid sample;

FIG. 15 shows an exploded view of a specific embodiment of an integrated lancet and electrode structure according to the present disclosure;

FIG. 16A andFIG. 16B show perspective views of a first extruded body (16A) and a first extruded body joined with a second extruded body (16B) in connection with the description of an integrated lancet and electrode structure according to the present disclosure;

FIG. 17A shows the first extruded body ofFIGS. 16A and 16B with adhesive material applied to facilitate the joining of the first extruded body with the second extruded body;FIG. 17B shows the first extruded body and the second extruded body joined via the adhesive material; a portion of the second extruded body is not shown so that the location of the adhesive material can be seen;

FIG. 18 shows portions of the integrated lancet and electrode structure shown inFIG. 15;

FIG. 19 shows two different perspective views of the housing for the integrated lancet and electrode structure shown inFIG. 15;

FIG. 20 shows two cross-section views of the integrated lancet and electrode structure shown inFIG. 15;

FIG. 21 shows two different side perspective views of an assembled version of the lancet and electrode structure shown inFIG. 15;

FIG. 22 shows two different bottom perspective views of an assembled version of the lancet and electrode structure shown inFIG. 15;

FIG. 23 shows first and second extruded bodies, wherein each of the first and second extruded bodies includes two conductive leads; a carbon based electrode ink is shown deposited over the conductive leads of the first extruded body to produce a working electrode; Ag/AgCl electrode ink is shown deposited over the conductive leads of the second extruded body to produce reference/counter and indicator electrodes;

FIG. 24 shows an embodiment of an integrated lancet and electrode structure according to the present disclosure, wherein the integrated lancet and electrode structure includes a first lumen and a second lumen, the first lumen having a larger diameter than the second lumen;FIG. 24 also shows an exemplary conductive material configuration for the integrated lancet and electrode structure;

FIG. 25 shows a top view of one half of the conductive material configuration shown inFIG. 24;

FIG. 26 shows an embodiment of an integrated lancet and electrode structure according to the present disclosure, wherein the integrated lancet and electrode structure includes a first lumen and a second lumen, the first lumen having approximately the same diameter as the second lumen;FIG. 26 also shows an exemplary conductive material configuration for the integrated lancet and electrode structure;

FIG. 27 shows a top view of one half of a conductive material configuration of an integrated lancet and electrode structure according to the present disclosure, wherein the integrated lancet and electrode structure includes a first lumen and a second lumen, the first lumen having approximately the same diameter as the second lumen;

FIG. 28 shows two integrated lancet and electrode structures stackably engaged with each other;

FIG. 29 shows a solid, cylindrical electrode structure in which a first conductive material and a second conductive material are coextruded with a dielectric material so as to provide a cylindrical electrode structure having a conductive center core and a conductive ring in a coaxial configuration;

FIG. 30 shows a solid, cylindrical electrode structure as shown inFIG. 29 wherein the second end of the electrode structure is modified via stripping of the dielectric material to provide greater surface area exposure for the coaxial conductive ring relative to the embodiment shown inFIG. 29;

FIG. 31 shows an embodiment, in which an end of a solid, cylindrical electrode structure is configured as a sensing end of an analyte sensor;

FIG. 32 shows a cross-section and a perspective view of an exemplary hollow electrode structure having a tubular configuration in accordance with the present disclosure;

FIG. 33 shows an exemplary hollow electrode structure having a tubular configuration as shown inFIG. 32, wherein the hollow electrode structure has cutouts which exposes a working electrode and a reference/counter electrode;

FIG. 34 shows a cross-section view of the sensor end of the hollow electrode structure shown inFIG. 33;

FIG. 35 shows a cross-sectional view of the connection end of the hollow electrode structure shown inFIG. 33;

FIG. 36 shows three different views of a hollow electrode structure which can be extruded as a unitary structure, modified with optional cutout regions, and cut to produce multiple electrode structures;

FIG. 37 shows views of the connection end of the hollow electrode structure shown inFIG. 36, including a cross-sectional view;

FIG. 38 shows views of the sensor end of the hollow electrode structure shown inFIG. 36, including a cross-sectional view;

FIG. 39 shows two different views of an exemplary hollow electrode structure having a tubular configuration in accordance with the present disclosure;

FIG. 40 shows an exemplary hollow electrode structure having a tubular configuration and an insertion needle;FIG. 40 also shows a connector suitable for connection to the hollow electrode structure;

FIG. 41 shows the exemplary hollow electrode structure ofFIG. 40 engaged with the connector ofFIG. 40.

FIG. 42 shows a photograph of a hollow electrode structure having a tubular configuration in accordance with the present disclosure;

FIG. 43 shows a photographic cross section of the hollow electrode structure shown inFIG. 42;

FIG. 44 shows a photograph of a hollow electrode structure and an insertion needle in accordance with the present disclosure;

FIG. 45 shows a photograph of a hollow electrode structure and an insertion needle in accordance with the present disclosure; wherein the hollow electrode structure includes a tapered tip;

FIG. 46 shows two views of an exemplary external configuration for a hollow electrode structure having a tapered tip and a flared end;

FIG. 47 shows an illustration of a hollow electrode structure having a tapered tip and engaged with a connector having electrode contacts for contacting the conductive materials of the hollow electrode structure;

FIG. 48 shows the hollow electrode structure and connector ofFIG. 47 engaged with an insertion needle and an insertion needle carrier;

FIG. 49 shows three views of a connection configuration in which an electrode structure according to the present disclosure, including a tapered tip, is configured for connection to a staggered connector;

FIG. 50 shows three views of a connection configuration involving an electrode structure, a primary connector and a secondary connector;

FIG. 51 shows an example of a connector for engaging an electrode structure according to the present disclosure, wherein the connector includes a first electrode contact and a second electrode contact for contacting a first conductive material and a second conductive material of electrode structure respectively; the connector includes screw threads for engaging corresponding screw threads on an additional device, e.g., a power source;

FIG. 52 shows an extruded analyte sensor according to the present disclosure, wherein the extruded analyte sensor includes a first conductive material which includes a working electrode and a second conductive material which includes a reference/counter electrode;

FIG. 53 shows the extruded analyte sensor ofFIG. 52 engaged with a sensor connector having a first electrode contact and a second electrode contact which contact the first conductive material and the second conductive material respectively when the sensor connector is engaged with the extruded analyte sensor; the sensor connector also includes a sensor connection hub which is configured to engage with an insulin delivery tube;

FIG. 54 shows another view of the extruded analyte sensor ofFIG. 53, which includes a septum which provides a seal for the sensor connection hub;

FIG. 55 shows the extruded analyte sensor ofFIG. 54 with a housing which engages the extruded analyte sensor and the sensor connector; the housing includes electrode contacts which contact the electrode contacts of the sensor connector;

FIG. 56 shows a sensor/tube mount engaged with the housing and sensor connection hub ofFIG. 55;

FIG. 57 shows an insulin delivery tube which includes a first conductive material and a second conductive material;

FIG. 58 shows the insulin delivery tube ofFIG. 57, wherein the insulin delivery tube is engaged with an insulin delivery tube mount and an attachment hub; the insulin delivery tube mount is configured to engage the sensor/tube mount shown inFIG. 56; the attachment hub is configured to engage the sensor connection hub shown inFIG. 56;

FIG. 59 shows another view of the insulin delivery tube, insulin delivery tube mount, and attachment hub shown inFIG. 58;

FIG. 60 shows a depiction of an integrated device, including an insulin delivery tube and an extruded analyte sensor as shown inFIGS. 52-59;

FIG. 61 shows the integrated device ofFIG. 60 prior to engagement of the insulin delivery tube mount with the sensor/tube mount; an insertion needle having an insertion needle handle is depicted which can be utilized to insert the extruded analyte sensor into the body of a subject and/or patient.

FIG. 62 shows an additional integrated electrode structure according to the present disclosure;

FIG. 63 provides an illustration of a method for inserting an electrode structure into subcutaneous tissue of a subject and/or patient;

FIG. 64 shows a block diagram of a data monitoring and management system according to the present disclosure;

FIG. 65 shows a block diagram of an embodiment of a data processing unit of the data monitoring and management system shown inFIG. 64;

FIG. 66 shows a block diagram of an embodiment the primary receiver unit of the data monitoring and management system shown inFIG. 64;

FIG. 67 is a raw linearity chart showing the results of linearity testing on extruded Pebax® working electrodes;

FIG. 68 shows a graphical representation of the results of linearity testing on extruded Pebax® working electrodes;

FIG. 69 shows graphical results of stability testing on extruded Pebax® working electrodes;

FIG. 70 provides a table which shows the results of resistivity measurements for three blended conductive polymer materials with different percentages of carbon blending;

FIG. 71 shows cyclic voltammetric graphs for the conductive materials used in FreeStyle® strips and the conductive materials used in two conductive polymers.

DETAILED DESCRIPTION OF THE INVENTION

Before exemplary embodiments are described, it is to be understood that this invention is not limited to particular exemplary embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.

It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an electrode structure” includes a plurality of such electrode structures and reference to “the analyte sensor” includes reference to one or more analyte sensors and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

Extruded Electrode Structures

The present disclosure provides electrode structures which include one or more conductive materials coextruded with one or more dielectric materials. For example, the electrode structures can include 1, 2, 3, 4, or more conductive materials coextruded with 1, 2, 3, 4, or more dielectric materials. In some embodiments, where the electrode structures include a plurality of coextruded conductive materials, at least one coextruded dielectric materials serves to electrically isolate the conductive materials from one another, i.e., at least one dielectric material is coextruded with the plurality of conductive materials such that the plurality of conductive materials are not in electrical communication.

Conductive Materials

A variety of conductive materials are known in the art which may be utilized in connection with the electrode structures of the present disclosure. Generally, the conductive materials should have relatively low electrical resistance and should be electrochemically inert over the potential range of the electrode structure during operation. Suitable conductors include, but are not limited to, gold, carbon, platinum, ruthenium dioxide and palladium, as well as other non-corroding materials known to those skilled in the art. A conductive material for use in the electrode structures of the present disclosure can be a combination of two or more conductive materials, e.g., a blend. An example of a suitable conductive epoxy is ECCOCOAT CT5079-3 Carbon-Filled Conductive Epoxy Coating (available from W.R. Grace Company, Woburn, Mass.).

In one embodiment, a carbon-blended polymer, e.g., a carbon-blended Pebax® (polyether block amides) polymer, is utilized to produce one or more conductive materials of the electrode structures described herein. In one embodiment, a carbon-blended polymer includes from about 7% to about 20% carbon, e.g., carbon black. For example a carbon-blended polymer for use in the disclosed conductive materials can include about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19% or about 20%. In one embodiment, a carbon-blended polymer suitable for use in the electrode structures described herein includes greater than 7% carbon, e.g., greater than 7% carbon black. For example, in such an embodiment, the carbon-blended polymer can include between about 8% and about 20% carbon (e.g., about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19% or about 20% carbon). In one particular embodiment, a carbon-blended Pebax® polymer having 10% carbon black is utilized. In another embodiment, a carbon-blended Pebax® polymer having 13% carbon black is utilized. Pebax® resin is available from Arkema Inc., Philadelphia, Pa.

Where a polymer is utilized in connection with one or more of the conductive materials, the polymer may be chosen so that the polymer can serve as a flux restricting agent thereby eliminating any potential need for a flux restricting membrane. The polymer may also be chosen for material characteristics that render the polymer relatively stiff when dry and relatively soft when wetted by various bodily fluids.

Conductive materials suitable for use in connection with the disclosed electrode configurations can be colored, e.g., to differentiate between a first conductive material and a second conductive material. In one such embodiment, the first conductive material includes a first color, the second conductive material includes a second color, and the first and second colors are different.

In some embodiments, as described herein, one or more conductive materials are coextruded with one or more dielectric materials.

Dielectric Materials

A variety of dielectric materials are known in the art which may be utilized in connection with the electrode structures of the present disclosure. Suitable dielectric materials include, for example, polymeric or plastic materials and ceramic materials. In some embodiments, the dielectric materials include non-conducting polymers such as polyethylene, polystyrene, polysulfone, and polypropylene. In one embodiment, a suitable dielectric material is a Pebax® polymer.

In some embodiments, the dielectric material or materials are flexible. For example, where an electrode structure as described herein is configured for implantation into a patient, the electrode structure may be made flexible (although rigid electrode structures may also be used for implantable electrode structures) to reduce pain to a patient and damage to the tissue caused by the implantation of and/or the wearing of the electrode structure. A flexible electrode structure can increases a patient's comfort and allow a wider range of activities. Suitable dielectric materials for a flexible electrode structure include, for example, non-conducting plastic or polymeric materials and other non-conducting, flexible, deformable materials. Examples of useful plastic or polymeric materials include thermoplastics such as polycarbonates, polyesters (e.g., Mylar™ and polyethylene terephthalate (PET)), polyvinyl chloride (PVC), polyurethanes, polyethers, polyamides, polyimides, or copolymers of these thermoplastics, such as PETG (glycol-modified polyethylene terephthalate).

In other embodiments, the electrode structures are made using relatively rigid dielectric materials, which, for example, provide structural support against bending or breaking. Examples of rigid dielectric materials include poorly conducting ceramics, such as aluminum oxide and silicon dioxide. Where an electrode structure is to be implanted, one advantage of using a rigid dielectric material is that the electrode structure may have a sharp point and/or a sharp edge to aid in implantation of the electrode structure without an additional insertion device.

It will be appreciated that for many electrode structures and electrode structure applications, both rigid and flexible electrode structures will operate adequately. The flexibility of the electrode structure may also be controlled and varied along a continuum by changing, for example, the composition and/or thickness of the substrate.

In addition to considerations regarding flexibility, it may be desirable, e.g., where the electrode structure is to be wholly or partially implanted under a skin layer of a subject, that the electrode structure include a dielectric material which is physiologically harmless or biocompatible, such as for example, a substrate approved by a regulatory agency or private institution for in vivo use. In some embodiments, suitable dielectric materials may include or be selected from one or more biocompatible materials. A variety of such materials are known in the art, including, but not limited to, High Strength Toughened Fluoropolymer (HSTF), available from WL Gore & Assoc. Inc., Elkton, Md.; and parylene-c.

In some embodiments, a semi-permeable dielectric material may be selected. In such embodiments, the dielectric material may serve as a membrane, e.g., a flux limiting membrane which is semi-permeable to an analyte, e.g., glucose.

In some embodiments of the electrode structures disclosed herein, one or more dielectric materials are coextruded with one or more conductive materials such that one or more of the dielectric materials electrically isolates one or more of the conductive materials.

Electrode Configurations

In one embodiment, an electrode structure according to the present disclosure includes a first conductive material, a second conductive material, and a dielectric material. The first conductive material, the second conductive material, and the dielectric material are coextruded to provide an electrode structure having the first conductive material and the second conductive material electrically isolated by the dielectric material.

The electrode structures described herein have broad utility and can be configured for a variety of in vitro and/or in vivo uses, including, but not limited to, use in analyte detection and/or monitoring, sample collection, and drug delivery. In some embodiments, at least a portion of the electrode structure is adapted for implantation in a subject. For example, the electrode structure can be configured such that at least a portion of the electrode structure can be subcutaneously positioned in a subject. The electrode structure may be wholly implantable in a user or may be configured so that only a portion is positioned within (internal) a user and another portion outside (external) a user. It should be noted that the terms “user,” “subject,” and “patient” are used interchangeably herein.

In some embodiments, a biocompatible dielectric material is included in the electrode structures. This biocompatible dielectric material can be coextruded with the two or more conductive materials and/or included as a biocompatible outer layer which at least partially encloses a coextruded layer including two or more conductive materials and one or more dielectric materials.

As indicated above, the electrode structures of the present disclosure can be configured as analyte sensors for use in analyte detection and/or monitoring. In some such embodiments, the electrode structure includes a first conductive material, a second conductive, and a dielectric material, wherein the first conductive material includes a working electrode and the second conductive material includes a reference/counter electrode.

The working electrode includes a conductive material and a sensing layer disposed on, in or proximate thereto, wherein the sensing layer is in electrical communication with the conductive material. The sensing layer may be described as the active chemical area of the analyte sensor. The sensing layer formulation, which can include an analyte-transducing agent/analyte-responsive agent (e.g., a glucose-transducing agent) may include, for example, among other constituents, a redox mediator, such as, for example, a hydrogen peroxide or a transition metal complex, such as a ruthenium-containing complex or an osmium-containing complex, and an analyte response enzyme, such as, for example, a glucose responsive enzyme (e.g., glucose oxidase, glucose dehydrogenase, etc.). The sensing layer may also include other optional components, such as, for example, a polymer and a bi-functional, short-chain, epoxide cross-linker, such as polyethylene glycol (PEG). In some embodiments, the sensing layer includes a metal nanopowder, such as aluminum nanopowder, iron nanopowder, copper nanopowder, nickel nanopowder, magnesium nanopowder, titanium nanopowder, or titanium nitride nanopowder.

In some embodiments, the sensing layer includes an analyte responsive enzyme which is capable of catalyzing a reaction of the analyte. The analyte responsive enzyme can also, in some embodiments, act as an electron transfer agent. There are a variety of suitable analyte responsive enzymes which can be utilized in the sensing layers described herein. For example, glucose oxidase or glucose dehydrogenase (e.g., pyrroloquinoline quinone (PQQ) dependent glucose dehydrogenase, flavine adenine dinucleotide (FAD) dependent glucose dehydrogenase, or nicotinamide adenine dinucleotide (NAD) dependent glucose dehydrogenase), may be used when the analyte of interest is glucose. A lactate oxidase or lactate dehydrogenase may be used when the analyte of interest is lactate. Laccase may be used when the analyte of interest is oxygen or when oxygen is generated or consumed in response to a reaction of the analyte. Nicotinamide adenine dinucleotide (NAD) dependent hydroxybutyrate dehydrogenase (HBDH) may be used where the analyte of interest is a ketone body.

In certain embodiments, an analyte responsive enzyme may be attached to a polymer, cross linking the analyte responsive enzyme with another electron transfer agent, which, as described below, may be polymeric. An additional catalyst may also be used in certain embodiments. This additional catalyst may be used, for example, to catalyze a reaction of a product compound resulting from the catalyzed reaction of the analyte. The additional catalyst may operate with an electron transfer agent to electrolyze the product compound to generate a signal at the working electrode. Alternatively, an additional catalyst may be provided in an interferent-eliminating layer to catalyze reactions that remove interferents.

In one embodiment, the analyte responsive enzyme is immobilized on an electrode. This is accomplished, for example, by cross linking the analyte responsive enzyme with a redox mediator on the electrode, thereby providing a sensing layer on the electrode, e.g., to create a working electrode.

In another embodiment, the analyte responsive enzyme is disposed adjacent to an electrode to create a working electrode. In such embodiments, the analyte responsive enzyme and redox mediator are generally positioned in close proximity to the electrode in order to provide for electrochemical communication between the analyte responsive enzyme, the redox mediator and the electrode.

In some embodiments, in order to facilitate the electrochemical reaction of the analyte sensor the sensing layer also includes an enzyme cofactor, such as nicotinamide adenine dinucleotide (NAD⁺) and/or flavin adenine dinucleotide (FAD). For example, where the analyte responsive enzyme is glucose dehydrogenase suitable cofactors include pyrroloquinoline quinone (PQQ), NAD⁺ and FAD. Additional analyte responsive enzymes and cofactors which may be used in connection with the disclosed sensors are described in U.S. Pat. No. 6,736,957, the disclosure of which is incorporated by reference herein.

A variety of analytes can be detected and quantified using the disclosed electrode structures. Analytes of particular interest include glucose and lactate. Additional analytes that may be determined include, for example, acetyl choline, amylase, bilirubin, cholesterol, chorionic gonadotropin, creatine kinase (e.g., CK-MB), creatine, DNA, fructosamine, glutamine, growth hormones, hormones, ketones (e.g., ketone bodies), oxygen, peroxide, prostate-specific antigen, prothrombin, RNA, thyroid stimulating hormone, and troponin. The concentration of drugs, such as, for example, antibiotics (e.g., gentamicin, vancomycin, and the like), digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may also be determined. Assays suitable for determining the concentration of DNA and/or RNA are disclosed in U.S. Pat. No. 6,281,006 and U.S. Pat. No. 6,638,716, the disclosures of each of which are incorporated by reference herein. An analyte monitoring system according to the present disclosure may be configured to monitor a variety of analytes at the same time or at different times.

As indicated above, in some embodiments, in addition to the analyte responsive enzyme, the sensing layer includes a redox mediator. The redox mediator mediates a current between the working electrode and the analyte when present, functioning as an electron transfer agent between the electrode and the analyte. In one embodiment, the redox mediator is immobilized on the working electrode. Materials and methods for immobilizing a redox mediator on an electrode are provided in U.S. Pat. No. 6,592,745, the disclosure of which is incorporated by reference herein. In another embodiment, the redox mediator is disposed adjacent to the working electrode.

Electron transfer agents that may be employed are electroreducible and electrooxidizable ions or molecules having redox potentials that are a few hundred millivolts above or below the redox potential of the standard calomel electrode (SCE). In some embodiments, electron transfer agents having a redox potential ranging from about −200 mV to about +200 mV versus the SCE are utilized. The electron transfer agent may be organic, organometallic, or inorganic. Examples of organic redox species are quinones and species that in their oxidized state have quinoid structures, such as Nile blue and indophenol. Examples of organometallic redox species are metallocenes including ferrocene. Examples of inorganic redox species are hexacyanoferrate (III), ruthenium hexamine etc. Additional examples include those described in U.S. Pat. No. 6,736,957 and U.S. Patent Publication Nos. 2004/0079653 and 2006/0201805, the disclosures of each of which are incorporated herein by reference.

In certain embodiments, electron transfer agents have structures or charges which prevent or substantially reduce the diffusional loss of the electron transfer agent during the period of time that the sample is being analyzed. For example, electron transfer agents include but are not limited to a redox species, e.g., bound to a polymer which can in turn be disposed on or near the working electrode. The bond between the redox species and the polymer may be covalent, coordinative, or ionic. Although any organic, organometallic or inorganic redox species may be bound to a polymer and used as an electron transfer agent, in certain embodiments the redox species is a transition metal compound or complex, e.g., osmium, ruthenium, iron, and cobalt compounds or complexes. It will be recognized that many redox species described for use with a polymeric component may also be used, without a polymeric component.

One type of polymeric electron transfer agent contains a redox species covalently bound in a polymeric composition. An example of this type of mediator is poly(vinylferrocene). Another type of electron transfer agent contains an ionically-bound redox species. This type of mediator may include a charged polymer coupled to an oppositely charged redox species. Examples of this type of mediator include a negatively charged polymer coupled to a positively charged redox species such as an osmium or ruthenium polypyridyl cation. Another example of an ionically-bound mediator is a positively charged polymer including quaternized poly(4-vinyl pyridine) or poly(1-vinyl imidazole) coupled to a negatively charged redox species such as ferricyanide or ferrocyanide. In other embodiments, electron transfer agents include a redox species coordinatively bound to a polymer. For example, the mediator may be formed by coordination of an osmium or

cobalt

2,2′-bipyridyl complex to poly(l-vinyl imidazole) or poly(4-vinyl pyridine).

Suitable electron transfer agents include osmium transition metal complexes with one or more ligands, each ligand having a nitrogen-containing heterocycle such as 2,2′-bipyridine, 1,10-phenanthroline, 1-methyl, 2-pyridyl biimidazole, or derivatives thereof. The electron transfer agents may also have one or more ligands covalently bound in a polymer, each ligand having at least one nitrogen-containing heterocycle, such as pyridine, imidazole, or derivatives thereof. One example of an electron transfer agent includes (a) a polymer or copolymer having pyridine or imidazole functional groups and (b) osmium cations complexed with two ligands, each ligand containing 2,2′-bipyridine, 1,10-phenanthroline, or derivatives thereof, the two ligands not necessarily being the same. Some derivatives of 2,2′-bipyridine for complexation with the osmium cation include but are not limited to 4,4′-dimethyl-2,2′-bipyridine and mono-, di-, and polyalkoxy-2,2′-bipyridines, including 4,4′-dimethoxy-2,2′-bipyridine. Derivatives of 1,10-phenanthroline for complexation with the osmium cation include but are not limited to 4,7-dimethyl-1,10-phenanthroline and mono, di-, and polyalkoxy-1,10-phenanthrolines, such as 4,7-dimethoxy-1,10-phenanthroline. Polymers for complexation with the osmium cation include but are not limited to polymers and copolymers of poly(1-vinyl imidazole) (referred to as “PVI”) and poly(4-vinyl pyridine) (referred to as “PVP”). Suitable copolymer substituents of poly(1-vinyl imidazole) include acrylonitrile, acrylamide, and substituted or quaternized N-vinyl imidazole, e.g., electron transfer agents with osmium complexed to a polymer or copolymer of poly(1-vinyl imidazole). In one specific embodiment, the redox mediator is 1,10 Phenanthrolene-5,6-dione (PQ).

In some embodiments, an analyte responsive enzyme as described herein is crosslinked to a redox polymer as described herein. Addition description of redox polymers, including redox polymers having analyte responsive enzymes crosslinked thereto, can be found in U.S. Pat. Nos. 5,262,035; 5,264,105; 6,605,200; 5,593,852; and 5,356,786; and U.S. patent application Ser. No. 12/051,835, filed Mar. 19, 2008; and Ser. No. 12/172,589, filed Jul. 14, 2008; the disclosures of each of which are incorporated by reference herein.

To prevent electrochemical reactions from occurring on portions of the working electrode not coated by the mediator, a dielectric may be deposited on the electrode over, under, or surrounding the region with the bound redox mediator. Suitable dielectric materials include, e.g., waxes and non-conducting organic polymers such as polyethylene. Dielectric may also cover a portion of the redox mediator on the electrode. The covered portion of the mediator will not contact the sample, and, therefore, will not be a part of the electrode's working surface.

Although it can be advantageous to minimize the amount of redox mediator used, the range for the acceptable amount of redox mediator typically has a lower limit. The minimum amount of redox mediator that may be used is the concentration of redox mediator that is necessary to accomplish the assay within a desirable measurement time period, for example, no more than about 5 minutes or no more than about 1 minute.

The electrode structure can be configured (e.g., by selection of redox mediator, positioning of electrodes, etc.) such that a sensor signal is generated at the working electrode with a measurement period of no greater than about 5 minutes and such that a background signal that is generated by the redox mediator is no more than five times a signal generated by oxidation or reduction of 5 mM glucose. In some embodiments, the analyte sensor is configured such that the background signal that is generated by the redox mediator is the same or less than the signal generated by oxidation or reduction of 5 mM glucose. In some embodiments, the background that is generated by the redox mediator is no more than 25% of the signal generated by oxidation or reduction of 5 mM glucose, e.g., no more than 20%, no more than 15% or no more than 5%.

As indicated above, in some embodiments in which the disclosed electrode structures are configured as analyte sensors, the electrode structures include a first conductive material, a second conductive material, and a dielectric material, wherein the first conductive material includes a working electrode and the second conductive material includes a reference/counter electrode. The term “reference/counter electrode” as used herein refers to an electrode which functions as a reference electrode, a counter electrode, or both a reference and a counter electrode. Generally, the analyte responsive enzyme and redox mediator are positioned relative to the reference and/or counter electrode such that electrochemical communication between the analyte responsive enzyme and the redox mediator and the reference and/or counter electrode is minimized. In one embodiment, the signal at the reference/counter electrode may correspond to background signal which may be removed from the analyte signal obtained from one or more working electrodes by, for example, subtracting the signal.

Where an extruded electrode structure as described herein has been configured for use as an in vivo analyte sensor, a mass transport limiting layer, e.g., an analyte flux modulating layer, may be included with the sensor to act as a diffusion-limiting barrier to reduce the rate of mass transport of the analyte, for example, glucose or lactate, into the region around the working electrode. The mass transport limiting layers are useful in limiting the flux of an analyte to a working electrode in an electrochemical sensor so that the sensor is linearly responsive over a large range of analyte concentrations and is easily calibrated. Mass transport limiting layers may include polymers and may be biocompatible. A mass transport limiting layer may provide many functions, e.g., biocompatibility and/or interferent-eliminating, etc.

In certain embodiments, a mass transport limiting layer is a membrane composed of crosslinked polymers containing heterocyclic nitrogen groups, such as polymers of polyvinylpyridine and polyvinylimidazole. Embodiments also include membranes that are made of a polyurethane, or polyether urethane, or chemically related material, or membranes that are made of silicone, and the like.FIG. 31 shows an exemplary embodiment including such a membrane.

A membrane may be formed by crosslinking in situ a polymer, modified with a zwitterionic moiety, a non-pyridine copolymer component, and optionally another moiety that is either hydrophilic or hydrophobic, and/or has other desirable properties, in an alcohol-buffer solution. The modified polymer may be made from a precursor polymer containing heterocyclic nitrogen groups. For example, a precursor polymer may be polyvinylpyridine or polyvinylimidazole. Optionally, hydrophilic or hydrophobic modifiers may be used to “fine-tune” the permeability of the resulting membrane to an analyte of interest. Optional hydrophilic modifiers, such as poly(ethylene glycol), hydroxyl or polyhydroxyl modifiers, may be used to enhance the biocompatibility of the polymer or the resulting membrane.

A membrane may be formed in situ by applying an alcohol-buffer solution of a crosslinker and a modified polymer over an enzyme-containing sensing layer and allowing the solution to cure for about one to two days or other appropriate time period. The crosslinker-polymer solution may be applied to the sensing layer by placing a droplet or droplets of the solution on the sensor, by dipping the sensor into the solution, or the like. Generally, the thickness of the membrane is controlled by the concentration of the solution, by the number of droplets of the solution applied, by the number of times the sensor is dipped in the solution, or by any combination of these factors. A membrane applied in this manner may have any combination of the following functions: (1) mass transport limitation, i.e., reduction of the flux of analyte that can reach the sensing layer, (2) biocompatibility enhancement, or (3) interferent reduction.

In certain embodiments, the sensing system detects hydrogen peroxide to infer glucose levels. For example, a hydrogen peroxide-detecting sensor may be constructed in which a sensing layer includes enzyme such as glucose oxidase, glucose dehydrogenase, or the like, and is positioned proximate to the working electrode. The sensing layer may be covered by one or more layers, e.g., a membrane that is selectively permeable to glucose. Once the glucose passes through the membrane, it is oxidized by the enzyme and reduced glucose oxidase can then be oxidized by reacting with molecular oxygen to produce hydrogen peroxide.

In some embodiments, electrode structures according to the present disclosure include an indicator element capable of providing a service history for an electrochemical sensor as described in U.S. patent application Ser. No. 12/431,669, filed Apr. 28, 2009, the disclosure of which is incorporated herein by reference.

In some embodiments, electrode structures according to the present disclosure include three or more electrically isolated conductive materials. In some such embodiments, a third conductive material is coextruded with first and second conductive materials. In one embodiment, the electrode structure includes first, second and third conductive materials, wherein the first and second conductive materials include working and reference/counter electrodes respectively and the third conductive material includes a fill-indicator electrode. In another embodiment, the third conductive material includes a thermistor or thermocouple.

In some embodiments, the electrode structures of the present disclosure have a solid or substantially solid configuration. In other embodiments, the electrode structures have a hollow configuration. The electrode structures of the present disclosure can be configured in a variety of shapes and sizes depending on the desired application. Where the electrode structures have a solid or substantially solid configuration, suitable shapes may include, for example, solid or substantially solid cylindrical configurations, or solid or substantially solid rectangular box configurations. Rectangular box configurations may have a configuration which is substantially rectangular. Similarly cylindrical configurations may have a configuration which is substantially cylindrical, and tubular configurations may have a configuration which is substantially tubular. Where the electrode structures have a hollow configuration they can be configured as tubes, i.e., hollow, elongated cylinders. Additional configurations are possible, including, but not limited to, hollow, elongated, rectangular, box configurations. Various configurations and suitable applications for the electrode structures are described in greater detail below with reference to the figures.

Extruded Electrode Structures for In Vitro Use

As indicated above, the present disclosure provides electrode structures, which, in some embodiments, are configured for in vitro use. As used herein, “in vitro use” refers to an extracorporeal use of the electrode structure. For example, use of an electrode structure to detect and/or quantify the level of an analyte in the blood of a subject, wherein the skin of the subject is lanced to produce a blood drop and the electrode structure is brought into contact with the blood drop, is considered an in vitro use. Thus, an electrode structure according to the present disclosure can be configured as an in vitro analyte sensor (i.e., a discrete monitoring sensor). A variety of suitable configurations is available for such electrode structures including, but not limited to, electrode structures having solid or substantially solid configurations, and electrode structures having hollow configurations. Exemplary embodiments of these configurations are described in greater detail below with reference to the figures.

Solid Configurations

In some embodiments, the electrode structures of the present disclosure have a solid or substantially solid configuration. One such embodiment is depicted inFIGS. 1A and 1B, which show anelectrode structure100, which includes a firstconductive material101, a secondconductive material102, and adielectric material103. Theelectrode structure100 depicted inFIGS. 1A and 1B also includes an optional thirdconductive material104. The conductive materials and the dielectric material are coextruded to provide an electrode structure having the firstconductive material101 and the secondconductive material102 electrically isolated by thedielectric material103. In the embodiment shown inFIGS. 1A and 1B, optionalconductive material104 is also electrically isolated bydielectric material103.

It is not necessary that the dielectric material completely surround the conductive materials in order to electrically isolate the conductive materials. Instead, the dielectric material may serve to separate portions of the conductive materials from each other while remaining portions of the conductive materials are separated via their physical spacing in the electrode configuration. For example, as shown inFIGS. 1A and 1B, the conductive materials (101,102 and104) can be separated from one another by thedielectric material103 as well as by the physical spacing of the conductive materials themselves. InFIGS. 1A and 1B, the firstconductive material101 is separated from the second and third conductive materials bydielectric material103. The firstconductive material101 is also separated form the second and third conductive materials (102 and104) by agap105 between the firstconductive material101 and the second and third conductive materials (102 and104). When the electrode structure is configured for use as an analyte sensor, this gap or space can provide a reaction chamber for reaction of a fluid sample with components of the analyte sensor.

In exemplary embodiments, the thickness of the reaction chamber is small to promote rapid electrolysis of the analyte, as more of the sample will be in contact with the electrode surface for a given sample volume. Typically, the thickness of the reaction chamber is no more than about 0.2 mm. In some embodiments, the thickness of the reaction chamber is no more than about 0.1 mm, no more than about 0.05 mm, or less.

Where the electrode structures have a solid or substantially solid configuration, suitable shapes may include, for example, solid or substantially solid cylindrical configurations; and solid or substantially solid rectangular box configurations.

The electrode structure ofFIGS. 1A and 1B can be configured for use as an analyte sensor. In such an embodiment, the firstconductive material101 can include a working electrode which includes a sensing layer disposed on, in or proximate thereto, the secondconductive material102 can include a reference/counter electrode, and the optional thirdconductive material104 can be configured as a fill-indicator electrode. Analyte sensors according to the present disclosure can be configured to measure the level of an analyte in a small sample volume, e.g., a sample volume of less than about 1 μL, e.g., no more than about 500 nL, no more than about 100 nL, no more than about 75 nL, or no more than about 50 nL.

Hollow Configurations

In some embodiments, the electrode structures of the present disclosure have a hollow configuration. In one such embodiment, as shown inFIG. 2, anelectrode structure100 according to the present disclosure includes a firstconductive material101, a secondconductive material102, and adielectric material103. The conductive materials and the dielectric material are coextruded to provide an electrode structure having the first conductive material and the second conductive material electrically isolated by the dielectric material. In addition, where the electrode structure has a hollow configuration, the electrode structure includes one ormore lumens106, where each of the one or more lumens includes afirst opening110, asecond opening111, and alumen wall107. In some embodiments, e.g., as shown inFIGS. 2-7, the lumen extends the length of the electrode structure with thefirst opening110 positioned at one end and thesecond opening111 positioned at the opposite end. In some embodiments, hollow electrode structures according to the present disclosure include multiple lumens, e.g., 2, 3, 4, or more lumens. The electrode structures can be configured such that these lumens extend the length of the electrode structures thereby providing multiple passageways through the electrode structures. The lumens described in connection with the embodiments discussed herein are not limited to a particular cross-sectional size or shape as a variety of different cross-sectional sizes and shapes may be utilized.

As with the solid configurations described above, a variety of configurations is possible for the hollow electrode structures described herein. These include, for example, rectangular box configurations and cylindrical configurations, among others.

InFIGS. 2-7, exemplary hollow, cylindrical configurations are described which are suitable, for example, for in vitro use. With reference toFIGS. 2-7, anelectrode structure100 is provided, wherein the firstconductive material101 and the secondconductive material102 are coextruded with thedielectric material103 such that each of the firstconductive material101, the secondconductive material102, and thedielectric material103 define a portion of alumen wall107.

FIGS. 2 and 3 show two different views of anelectrode structure100. In some embodiments, as shown inFIGS. 2 and 3, the electrode structure is extruded such that the surface area oflumen wall107 defined by firstconductive material101 is significantly greater than the surface area oflumen wall107 defined secondconductive material102. In addition, in the embodiment shown inFIGS. 2 and 3, thedielectric material103 defines a smaller portion of the surface area of thelumen wall107 relative to the portion defined by

conductive materials

101 and102.

In some embodiments, theelectrode structure100 includes a plurality of optional lancet stand-offs108. These lancet stand-offs allow theelectrode structure100 to be used with a lancet (not shown), e.g., a lancet designed to lance the skin of a patient in connection with the monitoring of glucose levels. The lancet stand-offs are positioned such that a lancet can slidably engage thelumen wall107 without simultaneously contacting

conductive materials

101 and102. This may be important, for example, where simultaneous contact between the lancet and

conductive materials

101 and102 would cause an electrical short. In the embodiment shown inFIGS. 2 and 3, the lancet stand-offs108 are portions of firstconductive material101 anddielectric material103 which extend inward towards the cylinder axis.

In one embodiment of theelectrode structure100, e.g., as shown inFIGS. 2 and 3, theelectrode structure100 is configured to detect and/or quantitate an analyte in a fluid sample. In such an embodiment, firstconductive material101 includes a working electrode and secondconductive material102 includes a reference/counter electrode. In such embodiments, the electrode structure can be configured such that a fluid sample is drawn through thelumen106 of the electrode structure by capillary action during analyte detection and/or quantitation. In these embodiments, thelumen106, or a portion thereof, provides a reaction chamber for reaction of the fluid sample with components of the analyte sensor.

In such embodiments, the dimensions of the reaction chamber can vary based on the volume of the lumen and the location of the sensing layer relative to the conductive materials. In one embodiment, the reaction chamber has a volume of about 75 nl to about 125 nl, e.g., about 80 nl to about 120 nl, about 85 nl to about 115 nl, about 90 nl to about 110 nl, about 95 nl to about 105 nl, or about 100 nl.

FIGS. 4 and 5 show two different views of a hollow,cylindrical electrode structure100 having alumen106 and alumen wall107. In some embodiments, as shown inFIGS. 4 and 5, the electrode structure is extruded such that the surface area oflumen wall107 defined by firstconductive material101 is significantly greater than the surface area oflumen wall107 defined secondconductive material102. In addition, in the embodiment shown inFIGS. 4 and 5, thedielectric material103 defines a smaller portion of the surface area of thelumen wall107 relative to the portion defined by

conductive materials

101 and102. The embodiment shown inFIGS. 4 and 5 differs from that shown inFIGS. 2 and 3 in that inFIGS. 4 and 5 thedielectric material103 makes up less of theouter surface109 of theelectrode structure100.

As with the electrode structure depicted inFIGS. 2 and 3, theelectrode structure100 shown inFIGS. 4 and 5 includes a plurality of optional lancet stand-offs108.

In one embodiment of theelectrode structure100 shown inFIGS. 4 and 5, theelectrode structure100 is configured to detect and/or quantitate an analyte in a fluid sample. In such an embodiment, firstconductive material101 includes a working electrode and secondconductive material102 includes a reference/counter electrode.

FIGS. 6 and 7 show two different views of another hollow,cylindrical electrode structure100 having alumen106 and alumen wall107. The embodiment shown inFIGS. 6 and 7 differ from those ofFIGS. 2-5 in that the surface area oflumen wall107 defined by firstconductive material101 is not significantly greater than the surface area oflumen wall107 defined by secondconductive material102. In addition, in the embodiment shown inFIGS. 6 and 7, thedielectric material103 does not defines a smaller portion of the surface area of thelumen wall107 relative to the portion defined by

conductive materials

101 and102. Finally, the embodiment shown inFIGS. 6 and 7 differs from those ofFIGS. 2-5 in that the optional lance stand-offs108 are formed fromdielectric material103 and not from either of

conductive materials

101 or102.

In one embodiment of theelectrode structure100 shown inFIGS. 6 and 7, theelectrode structure100 is configured to detect and/or quantitate an analyte in a fluid sample. In such an embodiment, firstconductive material101 includes a working electrode and secondconductive material102 includes a reference/counter electrode.

In some embodiments, where the hollow electrode structures are configured for in vitro use, they include a hole which extends through the dielectric material of the electrode structure and is at least substantially perpendicular to the lumen. This hole can be created in a variety of ways, including, but not limited to, mechanical or laser drilling. The hole can serve to disrupt the capillary effect that occurs when one end of the electrode structure is placed in contact with a fluid sample, e.g., a blood drop. The distance from the holes to the fluid sample-collecting end of the electrode structure can be selected so that the total uptake volume of fluid sample due the capillary effect can be controlled.

Additional components can be added to the hollow electrode structures to enhance their functionality. For example, in one embodiment, the electrode structure includes one or more rigid materials provided, e.g., embedded, in the dielectric material and coextruded with the first conductive material, the second conductive material, and the dielectric material. In one embodiment, the rigid material extends from the proximal end of an electrode structure having proximal and distal ends and functions as a lancet.

In another embodiment, the rigid material includes a third conductive material. This third conductive material can be the same or different as the first and second conductive materials which are coextruded with the dielectric material to produce the hollow electrode structure. In one embodiment, the one or more rigid materials include a third conductive material and the electrode structure includes a hole extending through the dielectric material and at least substantially perpendicular to the lumen. The hole exposes the one or more rigid materials which can serve as a fill indicator. In one such embodiment, when a fluid sample fills the electrode structure up to the hole, the fluid sample contacts the portion of the one or more rigid materials exposed by the hole thereby creating an electrical short which indicates filling of the electrode structure.

A variation on the embodiments shown inFIGS. 2-7 is provided inFIGS. 8 and 9.FIGS. 8 and 9 show two different views of anintegrated electrode structure200 which includes a firstconductive material201 and adielectric material202. The firstconductive material201 and thedielectric material202 are coextruded to provide an electrode structure which includes alumen203, wherein the lumen includes afirst opening206, asecond opening207 and alumen wall204. The firstconductive material201 and thedielectric material202 each define a portion of thelumen wall204, and the portion of thelumen wall204 defined by thedielectric material202 extends into the lumen beyond the portion oflumen wall204 defined by the firstconductive material201 thereby providing a dielectric stand-off.Integrated electrode structure200 also includes alancet205 which includes a second conductive material. Thelancet205 is slidably positioned within thelumen203 such that it contacts the portion oflumen wall204 defined by thedielectric material202 and not the portion oflumen wall204 defined by the firstconductive material201. In other words, the conductive lance is positioned to slidably engage the dielectric stand-off provided bydielectric material202.

In one embodiment, theintegrated electrode structure200 is configured to detect and/or quantitate an analyte in a fluid sample. In such an embodiment, the first conductive material includes a working electrode, and thelancet205 includes a reference/counter electrode.

Additional Configurations

Where the electrode structures are designed for in vitro use, a variety of additional configurations are possible. For example, in one embodiment, an electrode structure according to the present disclosure includes a first extruded body which includes a first conductive material coextruded with a first dielectric material. The electrode structure also includes a second extruded body which includes a second conductive material coextruded with a second dielectric material. The electrode structure is configured such that the first conductive material is electrically isolated from the second conductive material. In one such embodiment, the first extruded body and the second extruded body are snapedly engaged. One such embodiment is depicted inFIGS. 10,11A and11B.Electrode structure300 is formed by snapedly engaging firstextruded body301 with secondextruded body302.FIG. 10 shows first extrudedbody301 and secondextruded body302 prior to engagement.FIG. 11B shows firstextruded body301 positioned above secondextruded body302 prior to engagement to formelectrode structure300 as shown in Panel A. First extrudedbody301 includes a firstconductive material303 coextruded with a firstdielectric material306. Secondextruded body302 includes a secondconductive material304 coextruded with a seconddielectric material307. Optionally,electrode structure300 can include a thirdconductive material305 as depicted inFIG. 10.

In one embodiment, as an alternative, or in addition to, snapedly engaging firstextruded body301 with secondextruded body302, the two extruded bodies can be attached to each other via an adhesive material, or other suitable interlocking features.

In some embodiments, the electrode structure is configured to detect and/or quantitate an analyte in a fluid sample. In such embodiments, firstconductive material303 can include a working electrode, secondconductive material304 can include a reference/counter electrode, and thirdconductive material305 can include an indicator electrode when present. Agap308 provides a reaction chamber into which a fluid sample can be introduced for quantitation and/or analysis. When introduced into the reaction chamber, the fluid sample comes into electrolytic contact with the working electrode, the reference/counter electrode and optionally the indicator electrode when present.

In some embodiments, as shown inFIG. 10, firstextruded body301 includes ahole309.Hole309 is positioned such that when firstextruded body301 and secondextruded body302 are engaged,hole309 provides access to secondconductive material304, e.g., for connection to a power source and/or analyte meter. Similarly, secondextruded body302 can include

holes

310 and311, which provide access to firstconductive material303 and thirdconductive material305 respectively.

While the embodiment depicted inFIGS. 10 and 11 has been described with respect to coextruded structures, it should be noted that in alternative embodiments the conductive materials can be deposited on first and second engageable bodies using standard deposition techniques known in the art.

Integrated Electrode Structures for In Vitro Use

The present disclosure provides integrated electrode structures for in vitro use. In one such embodiment, an integrated lancet and electrode structure is provided. The integrated structure is configured to lance the skin of a subject thereby providing fluid, e.g., blood, for analysis using the integrated electrode structure. In one embodiment, as shown inFIGS. 12-14, an integrated lancet andelectrode structure400 includes a firstextruded body401 which includes a firstconductive material402 coextruded with a firstdielectric material403. The first extruded body defines a first channel (not shown). The integrated lancet and electrode structure also includes a secondextruded body404 which includes a secondconductive material405 coextruded with a seconddielectric material406. The second extruded body defines a second channel (not shown). The integrated lancet andelectrode structure400 is configured such that the firstconductive material402 is electrically isolated from the secondconductive material405 and the first and second channels together define alumen407 having afirst opening408 and asecond opening409. The integrated lancet and electrode structure includes alancet410 slidably positioned within thelumen407, wherein the lancet comprises alancet tip411. The integrated lancet andelectrode structure400 also includes ahousing412 and aspring413 positioned in thehousing412 and engaged with thelancet410, such that when thespring413 is compressed (FIGS. 13, A and B), thelancet410 extends through thelumen407 to expose thelancet tip411, and when thespring413 is uncompressed (FIGS. 13, C and D), thelancet tip411 is retracted to a position within thelumen407. As shown inFIGS. 12-14, anoptional lancet carrier414 coupled tolancet410 can be used to compressspring413 during the lancing process. In some embodiments, thespring413 is a molded component of thelancet carrier414. It should be noted that use of a spring is exemplary as a variety of structures could be utilized to facilitate movement of thelancet410 within thelumen407. For example, mechanical means such as a piston, rotating arm, etc., could be coupled to thelancet410 to facilitate movement of the lancet through thelumen407. Such mechanical means could be a component of the electrode structure or alternatively a component of a separate device configured to engage the electrode structure.

It should be noted that an integrated lancet and electrode structure could also be configured by modifying one or more of the electrode structures depicted inFIGS. 2-7 (i.e., electrode structures where the first conductive material, second conductive material and dielectric material are coextruded) to include a lancet. In one embodiment, one or more of the electrode structures depicted inFIGS. 2-7 is modified to include a lancet, a spring (or other suitable structure) and a housing as described with respect toFIGS. 12-14.

Specific embodiments of an integrated lancet and electrode structure are now described with reference toFIGS. 15-28. The integrated lancet andelectrode structure400 includes a firstextruded body401 which includes a firstconductive material402 coextruded with a firstdielectric material403. The first extruded body defines afirst channel415. The integrated lancet and electrode structure also includes a secondextruded body404 which includes a secondconductive material405 coextruded with a seconddielectric material406. The second extruded body defines asecond channel416. The integrated lancet andelectrode structure400 is configured such that the firstconductive material402 is electrically isolated from the secondconductive material405 and the first and second channels together define alumen407 having afirst opening408 and asecond opening409. The integrated lancet and electrode structure includes alancet410 slidably positioned within thelumen407, wherein thelancet410 comprises alancet tip411. Thelancet410 is slidably positioned within thelumen407, such that thelancet410 is capable of being extended through thelumen407 to expose thelancet410 and retracted to a position within thelumen407 such that thelancet410 is not exposed.

The integrated lancet andelectrode structure400 can also include ahousing412 and anoptional spring413 positioned in thehousing412 and engaged with thelancet410, such that when thespring413 is compressed, thelancet410 extends through thelumen407 to expose thelancet tip411, and when thespring413 is uncompressed, thelancet tip411 is retracted to a position within thelumen407.Housing412 includes anopening429 through whichlancet tip411 is exposed during the lancing process. Alancet carrier414 coupled tolancet410 can be used to compressspring413 during the lancing process. As indicated above, use of a spring is merely exemplary as a variety of structures could be utilized to facilitate movement of thelancet410 within thelumen407. For example, mechanical means such as a piston, rotating arm, etc., could be coupled to thelancet410 to facilitate movement of the lancet through thelumen407.

In the embodiment depicted inFIG. 15, theoptional spring413 is a molded component of thelancet carrier414, i.e., thespring413 and thelancet carrier414 are molded from the same material to produce a unitary structure. Furthermore, in the embodiment depicted inFIG. 15, an optional configuration is shown in which spring413 includes afirst spring arm417 and asecond spring arm418.

The embodiment depicted inFIG. 15 also includes anoptional bung419.Bung419 is slidably positioned within thelumen407. Thebung419 includes alumen420 with afirst opening421 and asecond opening422. The integrated lancet andelectrode structure400 is configured such that thelancet410 is slidably positioned within thelumen420.Bung419 operates as a lancet guide and to keep thelancet410 in a protected and/or sterile condition prior and/or subsequent to the lancing procedure. This can serve as a safety measure to prevent accidental contact with the lancet, e.g., by a user or health care provider. In exemplary embodiments,bung419 comprises an elastomeric material.

The embodiment depicted inFIG. 15 includes optional modifications to the structure of the extruded bodies. Specifically,FIG. 15 shows an embodiment in which the firstextruded body401 and the secondextruded body404 include athird channel423 and afourth channel424 respectively. Thethird channel423 and thefourth channel424 together define alumen425 having afirst opening426 and asecond opening427. Thislumen425 provides a path foroptional guide428 shown inFIG. 26. In some embodiments,lumen425 may also facilitate the capillary movement of fluid sample fromlumen407 into a reaction chamber where the fluid sample comes into electrolytic contact with a conductive material configured as a working electrode.Lumen425 can have the same or a different diameter aslumen407. In some embodiments, as shown inFIGS. 16A and 16B,lumen407 has a greater diameter thanlumen425. In other embodiments, as shown inFIGS. 26 and 27,lumen407 has the same diameter aslumen425.

FIGS. 16A and 16B shows firstextruded body401 individually (16A) and firstextruded body401 and secondextruded body404 positioned together (16B).

With reference toFIGS. 16A and 16B, an optional embodiment is disclosed wherein firstextruded body401 includes a secondconductive material430 which is coextruded withconductive material402 anddielectric material403. Similarly, secondextruded body404 includes a secondconductive material431 which is coextruded withconductive material405 anddielectric material406. This configuration provides two extruded bodies, wherein each extruded body includes two conductive leads. Portions of these conductive leads can be modified as discussed further herein to include working, reference/counter, and indicator electrodes.

In one embodiment,dielectric material403 anddielectric material406 are the same and include a polymeric base resin, e.g., polyamide (nylon) polyimide, polyvinylchloride, Pbax®, PTFE, and the like. The polymeric base resin can be coextruded with carbon filled polymeric base resin, e.g., carbon filled Pbax® to provide

conductive materials

402,405,430 and431.

The firstextruded body401 and secondextruded body404 are joined to produce an electrode

structure having lumens

407 and425. As shown inFIGS. 17A and17B, this can be accomplished via the use of anadhesive material432, e.g., two-sided tape, glue or epoxy. In some embodiments, the thickness of theadhesive material432 corresponds to the thickness of areaction chamber438 in which fluid sample comes into electrolytic contact with a working electrode. In exemplary embodiments, this thickness is small to promote rapid electrolysis of the analyte, as more of the sample will be in contact with the electrode surface for a given sample volume. Typically, the thickness of the reaction chamber is no more than about 0.2 mm. In some embodiments, the thickness of the reaction chamber is no more than about 0.1 mm, no more than about 0.05 mm, or less.

As indicated above, in some embodiments, integrated lancet andelectrode structure400 includes two extruded bodies, wherein each of the two extruded bodies includes two conductive leads. In one embodiment, these conductive leads are modified to include working, reference/counter, and indicator electrodes as shown inFIG. 23. For example, a carbon basedelectrode ink433 can be deposited over

conductive materials

402 and430 as shown inFIG. 23 to produce a working electrode. Similarly, Ag/AgCl electrode ink434 can be deposited over

conductive materials

405 and431 to produce reference/counter and indicator electrodes respectively. As shown inFIG. 23, there is a non-conductive space between the Ag/AgCl conductive ink deposited overconductive material405 and that deposited overconductive material431. This allows for the formation of two different electrodes, e.g., a reference/counter electrode and an indicator electrode.

It should be noted that while firstextruded body401 has been described above as including

conductive materials

402 and430, such a configuration is only exemplary. In other embodiments, a single conductive material is included in firstextruded body401 and carbon based electrode ink is deposited over the single conductive material to produce the working electrode.

With reference to, e.g.,FIGS. 21 and 25, the integrated lancet andelectrode structure400 can includeelectrode contacts435 which provide an electrical connection to a device of interest, e.g., an analyte meter.Electrode contacts435 can be configured in a variety of ways depending on the desired connection geometry. In some embodiments,electrode contacts435 are made up of the same materials used to extrude one or more of

conductive materials

402,430,405 and431.Contacts435 can also be coextruded as a portion of one or more of

conductive materials

402,430,405 and431.

In some embodiments, as shown inFIG. 26,lancet carrier414 includes aguide element428, which is configured to slidably engagelumen425. Theguide element428 may serve to stabilize engagement oflancet carrier414 with the electrode structure.

It may be of interest to configure an integrated lancet andelectrode structure400 such that multiple integrated lancet and electrode structure can be stackably engaged. In such an embodiment, as depicted inFIG. 28,housing412 can include one ormore protrusions436 positioned at the top end of a first integrated lancet andelectrode structure400. The one ormore protrusions436 can be configured to engage one or more indentations ornotches437 positioned at the bottom end of a second integrated lancet andelectrode structure400. These stackable integrated lancet and electrode structures may be useful for integration with an analyte meter configured to hold multiple integrated electrode structures. Stackable integrated lancet and electrode structures may also facilitate the packaging and/or sterilization of multiple integrated lancet and electrode structures.

Extruded Electrode Structures for In Vivo Use

The present disclosure provides extruded electrode structures, which, in some embodiments, are configured for in vivo use. As used herein, “in vivo use” refers to a use wherein the electrode structure is at least partially positioned within the body of a subject. For example, use of an electrode structure to detect and/or quantify the level of an analyte in the blood and/or interstitial fluid of a subject, wherein the electrode structure is at least partially implanted through the skin of the subject, is considered an in vivo use. Accordingly, the present disclosure includes analyte monitoring electrode structures (i.e., sensors) at least a portion of which are positionable beneath the skin surface of the user for the in vivo detection, of an analyte, including glucose, lactate, and the like, in a body fluid. Embodiments include wholly implantable analyte sensors and analyte sensors in which only a portion of the electrode structure is positioned under the skin surface and a portion of the electrode structure resides above the skin surface, e.g., for contact to a sensor control unit (which may include a transmitter), a receiver/display unit, transceiver, processor, etc. The sensor may be, for example, subcutaneously positionable in a patient for the continuous or periodic monitoring of a level of an analyte in a patient's interstitial fluid. For the purposes of this description, continuous monitoring and periodic monitoring will be used interchangeably, unless noted otherwise. The sensor response may be correlated and/or converted to analyte levels in blood or other fluids. In certain embodiments, an analyte sensor may be positioned in contact with interstitial fluid to detect the level of glucose, which detected glucose may be used to infer the glucose level in the patient's bloodstream. Analyte sensors may be insertable into a vein, artery, or other portion of the body containing fluid. Embodiments of the analyte sensors of the present disclosure may be configured for monitoring the level of the analyte over a time period which may range from seconds, minutes, hours, days, weeks, to months, or longer.

Many suitable configurations are available for the in vivo electrode structures described herein including, but not limited to, electrode structures having solid or substantially solid configurations, and electrode structures having hollow configurations. Exemplary embodiments of these configurations are described in greater detail below with reference to the figures.

Solid Configurations

Solid or substantially solid electrode configurations suitable for in vivo use can be prepared in a variety of configurations. For example, solid or substantially solid electrode structures suitable, for example, for in vivo use and having a cylindrical configuration are provided inFIGS. 29,30, and31.FIG. 29 shows a solid,cylindrical electrode structure500 in which firstconductive material501 and secondconductive material502 are coextruded with adielectric material503 so as to provide acylindrical electrode structure500 having a conductive center core and a conductive ring in a coaxial configuration. The conductive ring and the conductive center core are electrically isolated by thedielectric material503. In the embodiment shown inFIG. 29, firstconductive material501 is extruded as the conductive center core and secondconductive material502 is extruded as the coaxial conductive ring. It should be noted that this configuration can be reversed with firstconductive material501 being extruded as the coaxial conductive ring and secondconductive material502 being extruded as the conductive center core.

In addition, as shown inFIGS. 29-31, thedielectric material503 can be coextruded so as to cover the outside surface of the conductive ring as a protection and/or insulation measure. WhileFIGS. 29-31 illustrate cylindrical configurations including first and second conductive materials, it should be noted that these configurations can be readily modified to include third, fourth or nth conductive materials. In the context of the solid cylindrical configurations, these additional conductive materials can be included as additional coaxial conductive rings separated from each other by one or more dielectric materials.

In the embodiment shown inFIGS. 29 and 30, theelectrode structure500 includes an optional angled end or tip504 atfirst end505. As used herein, the terms “angled end” and “angled tip” are used interchangeably to refer to an end having an angle of less than 90° relative to the horizontal plane of the electrode structure (for example, the plane defined by the length of the electrode structure500). Inclusion of such an angled end serves to increase the exposed surface areas of the conductive materials relative to an end having a 90° angle relative to the horizontal plane of the electrode structure. In addition, depending on the properties of the conductive materials and/or the dielectric, e.g., depending on the rigidity, the angled end can serve as a sharp to facilitate insertion of the electrode structure through the skin layer of a subject and/or into, e.g., the tissue of the subject.

In one embodiment, as an alternative, or in addition to, inclusion of the angled end or tip atfirst end505, the various conductive layers can be exposed by stripping away portions of the dielectric material fromfirst end505 to create electrode surfaces in various geometries that can be exposed to the surrounding environment.

In some embodiments,second end506 of theelectrode structure500 includes a flat face having an at least substantially900 angle relative to the horizontal plane of the electrode structure as shown inFIG. 29. In such embodiments, the conductive core and the coaxial conductive ring are exposed atsecond end506 as shown inFIG. 29.

In other embodiments,second end506 is modified to provide greater exposure for the conductive core and/or the coaxial conductive ring. This can be accomplished, for example, by stripping thedielectric layers503 covering the conductive core and/or the coaxial conductive ring fromsecond end506 as shown inFIG. 30. Such modification configures each of the conductive materials for connection, e.g., to a connector or cable, which can simplify the manufacturing process and eliminate a potential need for keyed connectors commonly used for connection with some analyte sensors.

In some embodiments, theelectrode structure500 is configured for use as an analyte sensor. In these embodiments, the conductive core can be configured as a reference/counter electrode while the coaxial conductive ring is configured as a working electrode. Alternatively, the conductive core can be configured as a working electrode while the coaxial conductive ring is configured as a reference/counter electrode.

FIG. 31 shows a specific embodiment, in which firstconductive material501 is extruded as the conductive center core and secondconductive material502 is extruded as the coaxial conductive ring.First end505 ofelectrode structure500 is configured as a sensing end of the analyte sensor. In the method outlined inFIG. 31,dielectric material503 is removed fromfirst end505 to expose an area of the coaxial conductive ring (A). Theelectrode structure500 is contacted with a solution containing suitable sensing chemistry507 (B). The sensing chemistry solution is allowed to dry (C). Excess sensing chemistry is then removed from end505 (D) to expose the conductive center core and the coaxial conductive ring (E). Amembrane508 is applied to end505 (F) which covers the previously applied sensing chemistry as well as the exposed region of the conductive center core and the coaxial conductive ring (G and H). Application of the sensing chemistry toconductive material502, which has been extruded as the coaxial conductive ring, configuresconductive material502 as a working electrode.Conductive material501, which has not had the sensing chemistry applied, is available for use as a reference/counter electrode. In some embodiments, it may be desirable to add an additional conductive material, e.g. Ag/AgCl, toconductive material501 to configure it as a reference/counter electrode. This could be done, for example, prior to the addition ofsensing chemistry507 and/or prior to the addition ofmembrane508.

A variety of additional configurations for the solid or substantially solid electrode structures described herein are possible. These include, e.g., flexible or rigid configurations and configurations in the form of strings, strips or rods. In addition, whileFIGS. 29-31 depict electrode structures having conductive materials in coaxial configurations, it should be noted that non-coaxial embodiments are also possible. For example, in one such embodiment, the electrode structure can include a first conductive material in the form of a conductive stripe or zone and a second conductive material in the form of a conductive stripe or zone, wherein the first conductive material and the second conductive material are not positioned coaxially with respect to each other. In such an embodiment, the conductive materials are coextruded to provide an electrode structure have the first conductive material and the second conductive material electrically isolated by the dielectric material.

Hollow Configurations

Extruded, hollow electrode structures have wide applicability for in vivo use and can be prepared in a variety of configurations. For example,FIGS. 32-39 show exemplary hollow electrode structures having a tubular configuration. Thesetubular electrode structures600 include a firstconductive material601, a secondconductive material602, and adielectric material603. The firstconductive material601, the secondconductive material602, and thedielectric material603 are coextruded to provide anelectrode structure600 having the firstconductive material601 and the secondconductive material602 electrically isolated by thedielectric material603. Theelectrode structure600 includes alumen604, wherein the lumen includes afirst opening605, asecond opening606, and alumen wall607. In the embodiments shown inFIGS. 32-39, thedielectric material603 defines thelumen wall607, and the first and second conductive materials (601 and602) are provided, e.g., embedded or positioned, in thedielectric material603.

In some embodiments, e.g., as shown inFIGS. 32-39, the lumen extends the length of the electrode structure with thefirst opening605 positioned at one end and thesecond opening606 positioned at the opposite end. In some embodiments, hollow electrode structures according to the present disclosure include multiple lumens, e.g., 2, 3, 4, or more lumens. The electrode structures can be configured such that these lumens extend the length of the electrode structures thereby providing multiple passageways through the electrode structures. The lumens described in connection with the embodiments discussed herein are not limited to a particular cross-sectional size or shape as a variety of different cross-sectional sizes and shapes may be utilized.

In one embodiment, hollow electrode structures having a tubular configuration as described above have an outer diameter of about 0.60 mm to about 0.90 mm and a lumen diameter of about 0.40 mm to about 0.50 mm. For example, in some embodiments, a hollow electrode structure according to the present disclosure has an outer diameter of about 0.60 mm, 0.65 mm, 0.70 mm, 0.75 mm, 0.80 mm, 0.85 mm, or 0.90 mm. In some embodiments, a hollow electrode structure according to the present disclosure has a lumen diameter of about 0.40 mm, 0.45 mm, or 0.50 mm.

The length of the extruded, hollow electrode structures can vary significantly depending on the desired application. In some embodiments, an extruded, hollow electrode structure according to the present disclosure has a length of about 10 mm to about 20 mm, e.g., 15 mm.

The extruded electrode structures of the present disclosure can include one or more optional orientations features which allow a user and/or subject to differentiate between the first and second conductive materials. For example, the embodiment shown inFIG. 32 includes an optional orientation feature in the form of aplanar face608 which extends the length of the electrode structure. The positioning of the planar face allows a user and/or subject to determine the identity of the first and second conductive materials based on their position relative to theplanar face608.

As shown, for example, inFIGS. 32-39 electrode structures according to the present disclosure can be configured such that a firstconductive material601 and a secondconductive material602 extend the length of extrudedelectrode structure600. Such a configuration allows for the communication of electrical signals from one end of the electrode structure, e.g. a proximal end, to another end of the electrode structure, e.g. a distal end. Where the electrode structure is configured as an analyte sensor, such a configuration allows a sensor signal to be generated at one end of the electrode structure, e.g., an end inserted into the body of a subject, and communicated to another end of the electrode structure, e.g., an end positioned outside the body of the subject for connection to another device.

Differentiation between conductive materials, e.g., first and second conductive materials, can also be facilitated by configuring the conductive materials to include different colors which allow for visual differentiation between the conductive materials. This may be accomplished, for example, by including one or more dyes along with the conductive materials during the extrusion process. In some embodiments, the extrudedelectrode structure600 is configured as an analyte sensor, wherein the firstconductive material601 includes a working electrode and the secondconductive material602 includes a reference/counter electrode. In such embodiments, the working electrode includes a sensing layer disposed on, in or proximate thereto.

As shown inFIGS. 33 and 34, theelectrode structure600 can include afirst cutout609 in thedielectric material603 which exposes the working electrode and asecond cutout610 in thedielectric material603 which exposes the reference/counter electrode. These cutouts provide regions for contact between a sample, e.g., an analyte containing fluid, and the working and reference/counter electrodes. In addition, thecutout609 which exposes the working electrode provides a location for the deposition of the sensing layer of the working electrode.

In some embodiments, as shown for example inFIGS. 33 and 35,electrode structure600 includes athird cutout portion611 and afourth cutout portion612. Thethird cutout portion611 exposes a portion of the firstconductive material601 and thefourth cutout portion612 exposes a portion of the secondconductive material602.

Cutout portions

611 and612 provide exposed portions of their respective conductive materials which can facilitate electrical connection of the electrode structure to a device, e.g., electronics for processing signals from the analyte sensor such as, an analog interface including a potentiostat, a data processing component (such as one or more microprocessors), and/or a power source.

It should be noted that the dimensions of the cutout portions of the electrode structure can vary based on the particular application and/or connection intended for the electrode structure. The cutouts can be produced, for example, by cutting, drilling, laser etching, skiving, or any other suitable method. In some embodiments, the process used to produce the cutouts (or alternatively an independent process) can be used to manipulate the topography of one or more of the conductive materials exposed by the cutouts, for example, to manipulate the surface energy and/or increase the surface area of one or more of the conductive materials. For example, one or more hills, valleys, rows, etc., could be created in the surface of the conductive material exposed by a cutout to increase the surface area of the conductive material exposed by the cutout. Where the electrode structure is configured as an analyte sensor, such a manipulation of the electrode structure may serve to increase the sensitivity of the analyte sensor.

In some embodiments, where the electrode structure is configured as an analyte sensor, a membrane, e.g., a flux limiting membrane, may be disposed over the sensing layer. In such embodiments, a cutout exposing the sensing layer may be modified to facilitate retention of the membrane. For example, the cutout in the in the dielectric material can create one or more groves or channels in the dielectric material which facilitate retention of the membrane. In some embodiments, the membrane may be deposited as a liquid, e.g., in a dropwise manner, which subsequently solidifies forming the membrane. In such embodiments, the membrane may be effectively “locked” in position once it fills and then solidifies in the one or more grooves or channels created in the dielectric material.

The locations of the cutout portions of the electrode structure can also be varied depending on the particular application. For example, cutouts exposing the working and/or reference/counter electrode can be positioned in varying proximity to the proximal or distal end of electrode structure. In some embodiments, as shown inFIGS. 33 and 39,

cutouts

609 and610 are positioned at a proximal end ofelectrode structure600, while

cutouts

611 and612 are positioned at a distal end ofelectrode structure600.

For some embodiments, where the electrode structure is configured as an analyte sensor, use of a semi-permeable dielectric material may eliminate the need to expose a working electrode and/or a reference/counter electrode through the use of cutouts or other modification of the dielectric material as described above.

The hollow electrode structures described herein have a variety of potential uses and can be configured for use in any application where it would be desirable to utilize a tube having conductive capabilities, for example, as a medication delivery cannula/analyte sensor or as electrically conductive medical tubing. Where an electrode structure according to the present disclosure is configured as a medication delivery cannula/analyte sensor it may be desirable to position cutouts or other means of exposing the working and/or reference/counter electrode at a distance from a dispensing end of the medication delivery cannula. This allows for analyte detection at a distance from the point of medication delivery which may be beneficial where delivery of the medication causes a change in analyte concentration in the immediate vicinity. Accordingly, in some embodiments, cutouts or other means of exposing the working and/or reference/counter electrode are positioned at least 5 mm to at least 15 mm, e.g., 6 mm to 14 mm, 7 mm to 13 mm, 8 mm to 12 mm, 9 mm to 11 mm or 10 mm, from the site of medication delivery.

Insertion of Hollow Electrode Configurations

With reference toFIGS. 32-39,40,44, and45, insertion of anelectrode structure600 into the body of a subject can be accomplished via use of aninsertion needle613 which extends throughlumen604 ofelectrode structure600. After insertion is completed,insertion needle613 can be withdrawn, leaving at least a portion of theelectrode structure600 implanted or positioned under the skin surface in the body of the subject.

In some embodiments,electrode structure600 includes a taperedtip618, as shown inFIGS. 45 and 46, which can facilitate insertion, e.g., via aninsertion needle613 as described above.

Connection Geometry for Hollow Electrode Configurations

In some embodiments, a hollow electrode structure according to the present disclosure will be connected via a connector to one or more devices and/or power sources. Such a connector can be configured using any of a wide variety of suitable materials. For example, in one embodiment, a suitable connector includes an elastomeric material. Suitable connectors can include one or more conductive materials which serve as electrode contacts as described in more detail below. An exemplary connector embodiment is provided with reference toFIGS. 40 and 41, wherein theelectrode structure600 is configured to engage aconnector614. Theconnector614 includesfirst electrode contact615 andsecond electrode contact616 for engaging the firstconductive material601 and the secondconductive material602 respectively. As shown inFIGS. 40 and 41,connector614 also includesnon-conductive components617 separating

electrode contacts

615 and616.

FIG. 47 shows an embodiment in whichelectrode structure600, including a taperedtip618, is engaged withconnector614 havingfirst electrode contact615 andsecond electrode contact616.FIG. 48 shows a further embodiment, in which theelectrode structure600 depicted inFIG. 47 is engaged withinsertion needle613 andinsertion needle carrier619.

An additional connection configuration is depicted inFIG. 49. Anelectrode structure600, including a taperedtip618, is configured for connection to a staggered connector (not shown). Theelectrode structure600 includes a series ofelectrode contact bands620, e.g., gold electrode contact bands, which contact exposed portions ofconductive materials601 and602 (not shown inFIG. 49) in a staggered manner, e.g., at positions A and B respectively. The exposed portions of

conductive materials

601 and602 can be formed by skivingdielectric material603 in appropriate locations. The series ofelectrode contact bands620 are separated by a series of sealingrings621 which provide a sealed connection whenelectrode structure600 is inserted into a staggered connector (not shown).

FIG. 50 depicts a further connection configuration involving aprimary connector622 and asecondary connector623.Primary connector622 includes afirst electrode contact624 and asecond electrode contact625 which contact cutout portions ofelectrode structure600 such that

electrode contacts

624 and625 contact firstconductive material601 and secondconductive material602 respectively.Primary connector622 also includes sealing rings621 which provide for a sealed connection betweenprimary connector622 andsecondary connector623. Any suitable conductive material can be used forfirst electrode contact624 andsecond electrode contact625, including, e.g., gold plated electrode contacts.

Secondary connector

623 includes aconnector base626 and

electrode contacts

627 and628.Connector base626 can be injection molded and, in some embodiments, serves as an adhesive mount for attachment ofelectrode structure600 to a suitable surface, e.g., the skin of a subject and/or patient.

Electrode contacts

627 and628 can be made of any suitable conductive material, e.g., conductive silicone, and provide an electrical connection to

electrode contacts

624 and625 respectively. In another embodiment,first electrode contact624 andsecond electrode contact625 extend a sufficient distance fromprimary connector622 such that

electrode contacts

627 and628 are unnecessary and connection to a suitable device or power source can occur directly through

electrode contacts

624 and625.

In one embodiment, a connector for engaging anelectrode structure600 has the configuration set forth inFIG. 51, wherein aconnector700 includes afirst electrode contact701 and asecond electrode contact702 for contacting firstconductive material601 and the secondconductive material602 ofelectrode structure600 respectively.Connector700 includesscrew threads703 for engaging corresponding screw threads on a device and/or power source.

Integrated Electrode Structures for In vivo Use

With reference toFIGS. 52-61, an exemplary integrated device including analyte sensor and insulin delivery capabilities is now described.

FIG. 52 shows an extrudedanalyte sensor800, wherein the extrudedanalyte sensor800 includes a firstconductive material801 which includes a working electrode. The extrudedanalyte sensor800 also includes a second conductive material (not shown) which includes a reference/counter electrode. The first and second conductive materials are coextruded with adielectric material803 to produce an analyte sensor wherein firstconductive material801 and second conductive material802 are electrically isolated by thedielectric material803. The working electrode includes a sensing layer disposed on, in or proximate thereto.

Theanalyte sensor800 includes a lumen (not shown), wherein the lumen includes afirst opening805, asecond opening806, and a lumen wall (not shown). Thedielectric material803 defines the lumen wall, and the first and second conductive materials are provided, e.g., embedded or positioned, in thedielectric material803.

As shown inFIG. 52, the extrudedanalyte sensor800 includes afirst cutout808 in thedielectric material803 which exposes the working electrode and asecond cutout809 in thedielectric material803 which exposes the reference/counter electrode. These cutouts provide regions for contact between a sample, e.g., an analyte containing fluid, and the working and reference/counter electrodes. In addition, thecutout808 which exposes the working electrode provides a location for the deposition of the sensing layer of the working electrode.

As shown inFIG. 52, extrudedanalyte sensor800 includes athird cutout portion810 and afourth cutout portion811. Thethird cutout portion810 exposes a portion of the firstconductive material801 and thefourth cutout portion811 exposes a portion of the second conductive material802.

Cutout portions

810 and811 provide exposed portions of their respective conductive materials which facilitate electrical connection of the extrudedanalyte sensor800 to asensor connector812 as shown inFIG. 53.

FIG. 53 shows the extrudedanalyte sensor800 ofFIG. 52 engaged with asensor connector812.Sensor connector812 has afirst electrode contact813 and a second electrode contact (not shown) which contactconductive material801 and conductive material802 respectively whensensor connector812 is engaged with extrudedanalyte sensor800.Sensor connector812 also includes asensor connection hub815 which is configured to engage with an insulin delivery tube.Sensor connection hub815 includes aseptum816 as shown inFIG. 54, e.g., a silicon septum which may be a self-sealing septum, which provides a seal forsensor connection hub815.

Ahousing817, e.g., a silicon housing, engages the extrudedanalyte sensor800 and thesensor connector812, as shown inFIG. 55.Housing817 includes

electrode contacts

818 and819 which contactfirst electrode contact813 and a second electrode contact respectively.

A sensor/tube mount820 engageshousing817 andsensor connection hub815 as shown inFIG. 56. In some embodiments, sensor/tube mount820 includes an optional adhesive for attachment (not shown) to the body of a subject and/or patient.

FIG. 57 shows aninsulin delivery tube821. Like extrudedanalyte sensor800,insulin delivery tube821 includes a firstconductive material822 and a second conductive material (not shown). The first and second conductive materials can be coextruded with adielectric material824 to produce aninsulin delivery tube821 wherein firstconductive material822 and the second conductive material are electrically isolated by thedielectric material824.

Theinsulin delivery tube821 includes alumen825, wherein the lumen includes afirst opening826, asecond opening827, and a lumen wall (not shown). Thedielectric material824 defines the lumen wall (not shown), and the first and second conductive materials are provided, e.g., embedded, in thedielectric material824. Theinsulin delivery tube821 also includes

electrode contacts

829 and830 which contact the firstconductive material822 and the second conductive material823 respectively.

Electrode contacts

829 and830 are configured such that wheninsulin delivery tube821 is engaged withhousing817 andsensor connection hub815,electrode contact829

contacts electrode contact

818 andelectrode contact830

contacts electrode contact

819, thereby providing an electrical connection betweenconductive material822 andconductive material801, and between conductive material823 and conductive material802.

As shown inFIG. 58-60,insulin delivery tube821 is configured to engage an insulindelivery tube mount831 and anattachment hub832. Insulindelivery tube mount831 is configured to engage sensor/tube mount820, andattachment hub832 is configured to engagesensor connection hub815.Attachment hub832 includes aneedle833 which is designed to punctureseptum816 ofconnection hub815 upon engagement ofattachment hub832 withsensor connection hub815. A depiction of the integrated device, includingdelivery tube821 and extrudedanalyte sensor800, is provided inFIG. 60. As shown inFIG. 61, prior to engagement of insulindelivery tube mount831 with sensor/tube mount820, aninsertion needle834 having an insertion needle handle835 can be utilized to insert extrudedanalyte sensor800 into the body of a subject and/or patient.

While the integrated device depicted cumulatively inFIGS. 52-61 has been described herein for convenience as an integrated analyte sensor and insulin delivery device, it should be noted that the analyte sensor can be used to detect any of a wide variety of analytes and the integrated device can be used to delivery any of a wide variety of medications, drugs or therapeutic agents.

An additional integrated electrode structure according to the present disclosure is provided inFIG. 62. In this embodiment, anelectrode structure600 as described previously herein with reference toFIG. 45 is configured for insertion into a subject and/or patient through aninsertion pad900. Theinsertion pad900 includes aninsertion site901,electrode contact902,electrode contact903, and optional electronics (not shown) including, for example, an analog interface, one or more processors, etc., capable of receiving and/or processing sensor signals from

electrode contacts

902 and903. Theelectrode structure600 is modified to include acontact pad904, which includes

electrode contacts

905 and906. Upon insertion ofelectrode structure600 atinsertion site901,electrode contact905 comes into contact withelectrode contact902 andelectrode contact906 comes into contact withelectrode contact903, thereby providing a conductive path fromconductive material601 toelectrode contact902 and fromconductive material602 toelectrode contact903. As such, whereelectrode structure600 is configured as an analyte sensor, portions of theinsertion pad900 are in signal communication with the analyte sensor. Sensor signals received fromelectrode structure600 can be transmitted to a suitable receiver via the electronics including a transmitter, e.g., using an RF data transmission protocol.

As discussed above, in some embodiments extruded analyte sensors according to the present disclosure can be configured to deliver one or more medications through lumens of the analyte sensors. In some embodiments, the amount or dose of medication delivered is based at least in part on an analyte concentration determined using the analyte sensor. In some embodiments, it may be desirable to alternate and/or perform at different times the sensing and medication delivery functions of the extruded analyte sensor. For example, the analyte sensor can be configured such that it does not take an analyte reading during, or within a defined time period of, the period of time medication is actively being delivered to a subject through the lumen of the analyte sensor. A period of time can be selected which allows the subject's metabolism to adjust to the delivered medication such that an analyte measurement taken using the analyte sensor will be representative of the ambient analyte concentration. Such a defined time period can be, e.g., 1 to 5 sec, 5 to 10 sec, 10 to 20 sec, 20 to 30 sec, 30 to 40 sec, 40 to 50 sec or more; or 1 to 5 minutes or more. Such a configuration may prevent temporal alterations in analyte concentration, which may occur in the immediate vicinity of the analyte sensor upon medication delivery, from affecting the representative nature of the measured analyte concentration, e.g. where the measured glucose concentration is representative of the ambient glucose concentration of the subject.

Fill Assist

In some embodiments, the electrode structures described herein include one or more optional fill assist structures, e.g., one or more notches, cut-outs, indentations, and/or protrusions, which facilitate the collection of a fluid sample. For example, the analyte sensor can be configured such that the proximal end of the analyte sensor is narrower than the distal end of the analyte sensor. In one such embodiment, the analyte sensor comprises a tapered tip at the proximal end of the analyte sensor. Additional fill assist structures are described in U.S. Patent Publication No. 2008/0267823, the disclosure of which is incorporated by reference herein; and U.S. patent application Ser. No. 11/461,725, filed Aug. 1, 2006, the disclosure of which is incorporated by reference herein.

Fill Indicator Electrode

In some instances, it may be desirable to be able to determine when the reaction chamber is filled. Accordingly, the electrode structures can include a fill indicator, such as one or more indicator electrodes that can be used to determine when the reaction chamber has been filled. In some embodiments, conductive materials to be configured as one or more indicator electrodes will be coextruded along with the conductive materials to be configured as working and reference/counter electrodes. For example, with reference toFIG. 1, optional thirdconductive material104 can be configured as a fill-indicator electrode.

In the context of a hollow electrode structure, indicator electrodes can be prepared as follows. In one embodiment, a hollow electrode structure is formed such that third and fourth conductive materials are coextruded with first and second conductive materials, wherein the first and second conductive materials are to be configured as working and reference/counter electrodes respectively. The third and fourth conductive materials are provided, e.g., embedded or positioned, in dielectric material and located on opposite sides of a lumen from each other, such that a hole extending through the dielectric material and at least substantially perpendicular to the lumen exposes a portion of the third and fourth conductive material. In one such embodiment, when a fluid sample fills the electrode structure up to the hole, the fluid sample contacts the exposed portions of the third and fourth conductive materials thereby creating an electrical short which indicates filling of the electrode structure.

In some embodiments, when fluid reaches an indicator electrode, the signal from that electrode will change. Suitable signals for observing include, for example, voltage, current, resistance, impedance, or capacitance between the indicator electrode and, for example, working electrode. Alternatively, the sensor can be observed after filling to determine if a value of the signal (e.g., voltage, current, resistance, impedance, or capacitance) has been reached indicating that the reaction chamber is filled.

The electrode structure or equipment that the electrode structure is connected with (e.g., an analyte meter) can include a sign (e.g., a visual sign or auditory signal) that is activated in response to the indicator electrode to alert the user that the reaction chamber has been filled. The electrode structure or equipment can be configured to initiate a reading when the indicator electrode indicates that the reaction chamber has been filled with or without alerting the user. The reading can be initiated, for example, by applying a potential between the working electrode and the reference and/or counter electrode and beginning to monitor the signals generated at the working electrode. Additional description of fill indicator electrodes can be found in U.S. Pat. No. 6,592,745, the disclosure of which is incorporated by reference herein.

Method of Inserting an Electrode Structure into Subcutaneous Tissue of a Subject

With reference toFIG. 63, a method of inserting an electrode structure into subcutaneous tissue of a subject and/or patient is now described. In the embodiment, shown inFIG. 63, the method includes an insertion step in which acatheter1000 having acatheter assembly1001 is inserted into subcutaneous tissue of a subject and/or patient using aninsertion needle1002 positioned inside the catheter1000 (Panel A).Theinsertion needle1002 is subsequently removed from the subcutaneous tissue of the subject and/or patient (Panel B). Anelectrode structure1003 is then inserted into thecatheter1000 and attached to thecatheter assembly1001 such that a portion of theelectrode structure1003 is exposed to the subcutaneous tissue (Panel C).

Optionally, thecatheter assembly1001 can include anadhesive backing1004. Thisadhesive backing1004 can facilitate the attachment of thecatheter assembly1001 to the surface of the skin of a subject and/or patient. Accordingly, the above method can include an additional step of attaching the catheter assembly to the surface of the skin of the subject and/or patient, e.g. via contacting theadhesive backing1004 with the surface of the skin of the subject and/or patient.

In one embodiment, the electrode structure itself includes sensor electronics, e.g., a power supply, transmitter, etc. (not shown) (Panel C). In another embodiment, the catheter assembly includes the sensor electronics, e.g., a power supply, transmitter, etc. (not shown) (Panel D)coupled to the electrode structure.

It should be noted thatelectrode structure1003 is not limited to a particular electrode structure and any of the electrode structures described herein may be used or adapted for use with the above method. For example, the above method may be adapted for use with the hollow or solid electrode configurations described herein with respect to in vivo use.

Operation of Extruded Electrode Structures

Extruded electrode structures according to the present disclosure find use in a variety of applications, including, but not limited to, in vitro and in vivo analyte detection and/or monitoring.

In one embodiment, in the context of in vitro analyte detection and/or monitoring, a fluid sample is generally introduced into a reaction chamber of an extruded electrode structure and exposed to an analyte responsive enzyme and a redox mediator. A sensor signal is produced as a result of the interaction of the analyte responsive enzyme, the redox mediator, and the analyte when present. This signal can be communicated via one or more conductive materials of the electrode structure to an analyte meter designed to receive the sensor signal. In some embodiments, this communication occurs through one or more connectors which facilitate transfer of the sensor signal. The fluid sample can be provided by lancing the skin of a subject and/or patient to produce a blood drop which is then contacted by the electrode structure.

In one embodiment, in the context of in vivo analyte detection and/or monitoring, a portion of an extruded electrode structure is inserted into the tissue, e.g., the subcutaneous tissue, of a subject and/or patient. As described previously herein, the electrode structure can include an insertion needle and/or a tapered tip to facilitate the insertion process. Once the electrode structure is inserted, the internal environment of the tissue is generally exposed to an analyte responsive enzyme and a redox mediator located in a sensing layer disposed on, in, or in proximity to a working electrode. It should be noted that for in vivo purposes the electrode structure need not be completely inserted into the tissue of a patient. For example, the electrode can include a first portion which is designed for insertion into a tissue of a subject and/or patient and a second portion which is positioned outside the body of the subject and/or patient. This second portion can be designed to connect to an external device, e.g., an analyte monitoring device and/or a transmitter. In some embodiments, the electrode structure includes a portion positionable above a surface of the skin, and a portion positioned below the surface of the skin, e.g., penetrating through the skin and into, e.g., the subcutaneous space.

The length of the inserted portion of the extruded electrode structure can vary depending on the particular application. For example, in one embodiment, where the electrode structure is configured to operate as both an analyte sensor and a medication delivery tube, e.g., an insulin delivery tube, a portion of the electrode structure that is about 10 mm to about 15 mm in length is inserted into the tissue of a subject and/or patient. A portion of the electrode structure having a length of about 3 mm is positioned outside the body of the subject and/or patient for connection to an external device.

A sensor signal is produced as a result of the interaction of the analyte responsive enzyme, the redox mediator, and the analyte when present. This signal can be communicated via one or more conductive materials of the electrode structure to a device designed to receive the sensor signal. In some embodiments, this communication occurs through one or more connectors which facilitate transfer of the sensor signal. Details relating to the receipt of an analyte signal from an analyte sensor and the determination of a concentration of analyte are described, for example, in U.S. Pat. No. 7,041,468, the disclosure of which is incorporated by reference herein.

The disclosed electrode structures may be operated with or without applying a potential. In one embodiment, an electrochemical reaction occurs spontaneously at a working electrode and a reference/counter electrode provides a background signal.

In another embodiment, a potential is applied between the working and reference/counter electrodes. This potential does not need to remain constant. The magnitude of the required potential is dependent on the redox mediator. The potential at which the electrode poises itself, or where it is poised by applying an external bias, and where the analyte is electrolyzed is typically such that the electrochemical reaction is driven to or near completion. In some examples the electrochemical reaction is not oxidizing enough to result in significant electrochemical reaction of interferents, such as urate, ascorbate, and acetaminophen, that may affect the signal measured. For non-releasable redox mediators, the potential is typically between about −350 mV and about +400 mV versus the standard calomel electrode (SCE). In some exemplary embodiments, the potential of the redox mediator is more negative than +100 mV, e.g., the potential is more negative than0 mV. In some embodiments, the potential is about −150 mV versus SCE.

When an external potential is applied, it may be applied either before or after the sample has been placed in the electrode structure. In one embodiment, when a potential is applied and the sample is in a reaction chamber, an electrical current will flow between the working electrode and the reference/counter electrode. The current is a result, at least in part, of the electrolysis of the analyte in the sample. This electrochemical reaction occurs via the redox mediator and the optional second electron transfer agent. Examples of specific electrochemical reactions which can be utilized in connection with the disclosed analyte sensors are described in detail in U.S. Pat. No. 6,592,745, the disclosure of which is incorporated by reference herein.

A variety of measurement techniques may be utilized to detect and/or quantitate an analyte using the electrochemical signal generated by the sensor. These include, e.g., amperometry, coulometry, potentiometry, and/or voltometry, including square wave voltometry.

Self Powered Analyte Sensors

In some embodiments, where the electrode structures described herein are configured as analyte sensors, the electrode structures are configured for connection to an external power supply. In other embodiments, electrode structures configured as analyte sensors are self-powered. For example, the electrode structures described herein can be configured such that they spontaneously pass a current directly proportional to analyte concentration in the absence of an external power source, e.g., as described in U.S. patent application Ser. No. 12/393,921, filed Feb. 26, 2009, the disclosure of which is incorporated by reference herein.

Data Monitoring and Management System

The electrode structures described herein can be configured for use in a data monitoring and management system.FIG. 64 shows a data monitoring and management system such as, for example, an analyte (e.g., glucose)monitoring system2000 in accordance with certain embodiments. Embodiments of the present disclosure are further described primarily with respect to glucose monitoring devices and systems, and methods of glucose detection, for convenience only and such description is in no way intended to limit the scope of the invention. It is to be understood that the analyte monitoring system may be configured to monitor a variety of analytes at the same time or at different times.

Theanalyte monitoring system2000 includes asensor unit2001, which includes an extruded electrode structure as described herein, adata processing unit2002 connectable to thesensor unit2001, and aprimary receiver unit2004 which is configured to communicate with thedata processing unit2002 via acommunication link2003. In certain embodiments, theprimary receiver unit2004 may be further configured to transmit data to adata processing terminal2005 to evaluate or otherwise process or format data received by theprimary receiver unit2004. Thedata processing terminal2005 may be configured to receive data directly from thedata processing unit2002 via a communication link which may optionally be configured for bi-directional communication. Further, thedata processing unit2002 may include a transmitter or a transceiver to transmit and/or receive data to and/or from theprimary receiver unit2004 and/or thedata processing terminal2005 and/or optionally thesecondary receiver unit2006.

Only onesensor unit2001,data processing unit2002 anddata processing terminal2005 are shown in the embodiment of theanalyte monitoring system2000 illustrated inFIG. 64. However, it will be appreciated by one of ordinary skill in the art that theanalyte monitoring system2000 may include more than onesensor unit2001 and/or more than onedata processing unit2002, and/or more than onedata processing terminal2005. Multiple sensors may be positioned in a patient for analyte monitoring at the same or different times. In certain embodiments, analyte information obtained by a first positioned sensor may be employed as a comparison to analyte information obtained by a second sensor. This may be useful to confirm or validate analyte information obtained from one or both of the sensors. Such redundancy may be useful if analyte information is contemplated in critical therapy-related decisions. In certain embodiments, a first sensor may be used to calibrate a second sensor.

Theanalyte monitoring system2000 may be a continuous monitoring system, or semi-continuous, or a periodic monitoring system. In a multi-component environment, each component may be configured to be uniquely identified by one or more of the other components in the system so that communication conflict may be readily resolved between the various components within theanalyte monitoring system2000. For example, unique IDs, communication channels, and the like, may be used.

In certain embodiments, thesensor unit2001 is physically positioned in or on the body of a user whose analyte level is being monitored. Thesensor unit2001 may be configured to at least periodically sample or detect the analyte level of the user and generate a corresponding signal which may be processed by thedata processing unit2002 for transmission. Thedata processing unit2002 is coupleable to thesensor unit2001 so that both devices are positioned in or on the user's body, with at least a portion of theanalyte sensor unit2001 positioned transcutaneously.

Thedata processing unit2002 may include a fixation element such as adhesive or the like to secure it to the user's body. A mount (not shown) attachable to the user and mateable with thedata processing unit2002 may be used. For example, a mount may include an adhesive surface for adhering to the skin surface of the user. Thedata processing unit2002 performs data processing functions, where such functions may include but are not limited to, filtering and encoding of data signals, corresponding to sampled analyte levels of the user, for transmission to theprimary receiver unit2004 via thecommunication link2003. In one embodiment, thesensor2001 or thedata processing unit2002 or a combined sensor/data processing unit may be wholly implantable under the skin layer of the user.

In certain embodiments, theprimary receiver unit2004 may include an RF receiver and an antenna that is configured to communicate with thedata processing unit2002 via thecommunication link2003, and a data processing section for processing the received data from thedata processing unit2002 including data decoding, error detection and correction, data clock generation, data bit recovery, etc., or any combination thereof.

In operation, theprimary receiver unit2004 in certain embodiments is configured to synchronize with thedata processing unit2002 to uniquely identify thedata processing unit2002, based on, for example, an identification information of thedata processing unit2002, and thereafter, to periodically receive signals transmitted from thedata processing unit2002 associated with the monitored analyte levels detected by thesensor2001.

Referring again toFIG. 64, thedata processing terminal2005 may include a personal computer, a portable computer including a laptop or a handheld device (e.g., personal digital assistants (PDAs), telephone including a cellular phone (e.g., a multimedia and Internet-enabled mobile phone including an iPhone™, a Palm based mobile telephone, a Blackberry® device, or similar communication device), mp3 player, pager, iPOD™ and the like), drug delivery device, each of which may be configured for data communication with the receiver via a wired or a wireless connection. Additionally, thedata processing terminal2005 may further be connected to a data network (not shown) for storing, retrieving, updating, and/or analyzing data corresponding to the detected analyte level of the user. Thedata processing terminal2005 may include an infusion device such as an insulin infusion pump or the like, which may be configured to administer insulin to patients, and which may be configured to communicate with theprimary receiver unit2004 for receiving, among others, the measured analyte level. Alternatively, theprimary receiver unit2004 may be configured to integrate an infusion device therein so that theprimary receiver unit2004 is configured to administer insulin (or other appropriate drug) therapy to patients, for example, for administering and modifying basal profiles, as well as for determining appropriate boluses for administration based on, among others, the detected analyte levels received from thedata processing unit2002. An infusion device may be an external device or an internal device (wholly implantable in a user).

In certain embodiments, thedata processing terminal2005, which may include an insulin pump, may be configured to receive the analyte signals from thedata processing unit2002, and thus, incorporate the functions of theprimary receiver unit2004 including data processing for managing the patient's insulin therapy and analyte monitoring. In certain embodiments, thecommunication link2003 as well as one or more of the other communication interfaces shown inFIG. 64, may use one or more of: an RF communication protocol, an infrared communication protocol, a Bluetooth enabled communication protocol, an 802.1x wireless communication protocol, or an equivalent wireless communication protocol which would allow secure, wireless communication of several units (for example, per HIPPA requirements), while avoiding potential data collision and interference.

FIG. 65 shows a block diagram of an embodiment of adata processing unit2002 of the data monitoring anddetection system2000 shown inFIG. 64. User input and/orinterface components3002 may optionally be included or adata processing unit2002 may be free of user input and/or interface components. In certain embodiments, one or more application-specific integrated circuits (ASIC) may be used to implement one or more functions or routines associated with the operations of thedata processing unit2002. Thedata processing unit2002 includes one or more of: auser input3002, an RF transmitter/receiver3005, atemperature measurement section3003, aclock3007, and apower supply3006, each of which is operatively coupled to aprocessor3004.

As can be seen in the embodiment ofFIG. 65, the sensor unit2001 (FIG. 64) includes two electrodes—working electrode (W)3008, and reference/counter electrode (R/C)3009, each operatively coupled to theanalog interface3001 of thedata processing unit2002. Fewer or greater electrodes may be employed. For example, there may be more than one working electrode and/or reference/counter electrode, etc.

FIG. 66 is a block diagram of an embodiment of a receiver unit such as theprimary receiver unit2004 of the data monitoring and management system shown inFIG. 64. Theprimary receiver unit2004 includes one or more of: a blood glucosetest strip interface4001, anRF receiver4002, auser input4003, atemperature measurement section4004, and aclock4005, each of which is operatively coupled to a processing andstorage section4007. Theprimary receiver unit2004 also includes apower supply4006 operatively coupled to a power conversion andmonitoring section4008. Further, the power conversion andmonitoring section4008 is also coupled to the processing andstorage unit4007. Moreover, also shown are a receiverserial communication section4009, and an output/display4010, each operatively coupled to the processing andstorage unit4007. The receiver may include user input and/or interface components or may be free of user input and/or interface components.

In certain embodiments, thetest strip interface4001 includes a glucose level testing portion to receive a blood (or other body fluid sample) glucose test or information related thereto. For example, the interface may include a test strip port to receive a glucose test strip. The device may determine the glucose level of the test strip, and optionally display (or otherwise notice) the glucose level on the output/display4010 of theprimary receiver unit2004. Any suitable test strip may be employed, e.g., test strips that only require a very small amount (e.g., one microliter or less, e.g., 0.5 microliter or less, e.g., 0.1 microliter or less), of applied sample to the strip in order to obtain accurate glucose information, e.g. FreeStyle® blood glucose test strips from Abbott Diabetes Care Inc. The terms “test strip” and “glucose test strip” are used here for convenience. However, it should be noted that analyte sensors having extruded electrode structures in a variety of configurations as described herein, e.g., tubular or cylindrical configurations, can be configured to interface with the test strip interface of theprimary receiver unit2004. Glucose information obtained by the in vitro glucose testing device may be used for a variety of purposes, computations, etc. For example, the information may be used to calibrate sensor unit2001 (FIG. 64), confirm results of thesensor unit2001 to increase the confidence thereof (e.g., in instances in which information obtained bysensor2001 is employed in therapy related decisions), etc.

In further embodiments, the data processing unit2002 (FIG. 64) and/or the primary receiver unit2004 (FIG. 64) and/or the secondary receiver unit2006 (FIG. 64), and/or the data processing terminal/infusion section2005 (FIG. 64) may be configured to receive the blood glucose value wirelessly over a communication link from, for example, a blood glucose meter. In further embodiments, a user manipulating or using the analyte monitoring system2000 (FIG. 64) may manually input the blood glucose value using, for example, a user interface (e.g., a keyboard, keypad, voice commands, and the like) incorporated in one or more of thedata processing unit2002, theprimary receiver unit2004, thesecondary receiver unit2006, or the data processing terminal/infusion section2005.

Additional detailed descriptions are provided in U.S. Pat. Nos. 5,262,035; 5,262,305; 5,264,104; 5,262,305; 5,320,715; 5,593,852; 6,103,033; 6,134,461; 6,175,752; 6,560,471; 6,579,690; 6,605,200; 6,654,625; 6,746,582; 6,932,894; 6,284,478; 7,299,082; and in U.S. Patent Application Publication Nos. 2004/0186365 and 2004/0186365, the disclosures of each of which are herein incorporated by reference.

Sensor Control Unit

Where the extruded electrode structures of the present disclosure are configured to operate as in vivo analyte sensors, they can be configured to operate with one or more sensor control units. The sensor can be integrated in the sensor control unit, part or all of which may be subcutaneously implanted or it can be configured to be placed on the skin of a patient. The sensor control unit is optionally formed in a shape that is comfortable to the patient and which may permit concealment, for example, under a patient's clothing. The thigh, leg, upper arm, shoulder, and abdomen are convenient parts of the patient's body for placement of the sensor control unit to maintain concealment. However, the sensor control unit may be positioned on other portions of the patient's body. One embodiment of the sensor control unit has a thin, oval shape to enhance concealment. However, other shapes and sizes may be used.

The particular profile, as well as the height, width, length, weight, and volume of the sensor control unit may vary and depends, at least in part, on the components and associated functions included in the sensor control unit. In general, the sensor control unit includes a housing typically formed as a single integral unit that rests on the skin of the patient. The housing typically contains most or all of the electronic components of the sensor control unit.

The housing of the sensor control unit may be formed using a variety of materials, including, for example, plastic and polymeric materials, particularly rigid thermoplastics and engineering thermoplastics. Suitable materials include, for example, polyvinyl chloride, polyethylene, polypropylene, polystyrene, ABS polymers, and copolymers thereof. The housing of the sensor control unit may be formed using a variety of techniques including, for example, injection molding, compression molding, casting, and other molding methods. Hollow or recessed regions may be formed in the housing of the sensor control unit. The electronic components of the sensor control unit and/or other items, including a battery or a speaker for an audible alarm, may be placed in the hollow or recessed areas.

The sensor control unit is typically attached to the skin of the patient, for example, by adhering the sensor control unit directly to the skin of the patient with an adhesive provided on at least a portion of the housing of the sensor control unit which contacts the skin or by suturing the sensor control unit to the skin through suture openings in the sensor control unit.

When positioned on the skin of a patient, the sensor and the electronic components within the sensor control unit are coupled via conductive contacts. The working electrode and reference/counter electrode are attached to individual conductive contacts. For example, the conductive contacts can be provided on the interior of the sensor control unit. Other embodiments of the sensor control unit have the conductive contacts disposed on the exterior of the housing. The placement of the conductive contacts is such that they are in contact with the conductive contacts on the sensor when the sensor is properly positioned within the sensor control unit.

Sensor Control Unit Electronics

The sensor control unit also typically includes at least a portion of the electronic components that make up the analyte monitoring system. The electronic components of the sensor control unit typically include a power supply for operating the sensor control unit, a sensor circuit for obtaining signals from the sensor, a measurement circuit that converts sensor signals to a desired format, and a processing circuit that, at minimum, obtains signals from the sensor circuit and/or measurement circuit and provides the signals to an optional receiver. In some embodiments, the processing circuit may also partially or completely evaluate the signals from the sensor and convey the resulting data to the optional receiver and/or activate an optional alarm system if the analyte level exceeds a threshold. The processing circuit often includes analog and/or digital logic circuitry.

The sensor control unit may optionally contain a transmitter for transmitting the sensor signals or processed data from the processing circuit to a receiver/display unit; a data storage unit for temporarily or permanently storing data from the processing circuit; a temperature probe circuit for receiving signals from and operating a temperature probe; a reference voltage generator for providing a reference voltage for comparison with sensor-generated signals; and/or a watchdog circuit that monitors the operation of the electronic components in the sensor control unit.

Moreover, the sensor control unit may also include digital and/or analog components utilizing semiconductor devices, including transistors. To operate these semiconductor devices, the sensor control unit may include other components including, for example, a bias control generator to correctly bias analog and digital semiconductor devices, an oscillator to provide a clock signal, and a digital logic and timing component to provide timing signals and logic operations for the digital components of the circuit.

As an example of the operation of these components, the sensor circuit and the optional temperature probe circuit provide raw signals from the sensor to the measurement circuit. The measurement circuit converts the raw signals to a desired format, using for example, a current-to-voltage converter, current-to-frequency converter, and/or a binary counter or other indicator that produces a signal proportional to the absolute value of the raw signal. This may be used, for example, to convert the raw signal to a format that can be used by digital logic circuits. The processing circuit may then, optionally, evaluate the data and provide commands to operate the electronics.

Calibration

Sensors may be configured to require no system calibration or no user calibration. For example, a sensor may be factory calibrated and need not require further calibrating. In certain embodiments, calibration may be required, but may be done without user intervention, i.e., may be automatic. In those embodiments in which calibration by the user is required, the calibration may be according to a predetermined schedule or may be dynamic, i.e., the time for calibration may be determined by the system on a real-time basis according to various factors, including, but not limited to, glucose concentration and/or temperature and/or rate of change of glucose, etc.

In addition to a transmitter, an optional receiver may be included in the sensor control unit. In some cases, the transmitter is a transceiver, operating as both a transmitter and a receiver. The receiver may be used to receive calibration data for the sensor. The calibration data may be used by the processing circuit to correct signals from the sensor. This calibration data may be transmitted by the receiver/display unit or from some other source such as a control unit in a doctor's office. In addition, the optional receiver may be used to receive a signal from the receiver/display units to direct the transmitter, for example, to change frequencies or frequency bands, to activate or deactivate the optional alarm system and/or to direct the transmitter to transmit at a higher rate.

Calibration data may be obtained in a variety of ways. For instance, the calibration data may simply be factory-determined calibration measurements which can be input into the sensor control unit using the receiver or may alternatively be stored in a calibration data storage unit within the sensor control unit itself (in which case a receiver may not be needed). The calibration data storage unit may be, for example, a readable or readable/writeable memory circuit.

Calibration may be accomplished using an in vitro test strip (or other reference), e.g., a small sample test strip such as a test strip that requires less than about 1 microliter of sample (e.g., FreeStyle® blood glucose monitoring test strips from Abbott Diabetes Care). In some embodiments, test strips that require less than about 1 nanoliter of sample may be used. In certain embodiments, a sensor may be calibrated using only one sample of body fluid per calibration event. For example, a user need only lance a body part one time to obtain sample for a calibration event (e.g., for a test strip), or may lance more than one time within a short period of time if an insufficient volume of sample is firstly obtained. Embodiments include obtaining and using multiple samples of body fluid for a given calibration event, where glucose values of each sample are substantially similar. Data obtained from a given calibration event may be used independently to calibrate or combined with data obtained from previous calibration events, e.g., averaged including weighted averaged, etc., to calibrate. In certain embodiments, a system need only be calibrated once by a user, where recalibration of the system is not required.

Alternative or additional calibration data may be provided based on tests performed by a doctor or some other professional or by the patient. For example, it is common for diabetic individuals to determine their own blood glucose concentration using commercially available testing kits. The results of this test is input into the sensor control unit either directly, if an appropriate input device (e.g., a keypad, an optical signal receiver, or a port for connection to a keypad or computer) is incorporated in the sensor control unit, or indirectly by inputting the calibration data into the receiver/display unit and transmitting the calibration data to the sensor control unit.

Other methods of independently determining analyte levels may also be used to obtain calibration data. This type of calibration data may supplant or supplement factory-determined calibration values.

In some embodiments of the invention, calibration data may be required at periodic intervals, for example, every eight hours, once a day, or once a week, to confirm that accurate analyte levels are being reported. Calibration may also be required each time a new sensor is implanted or if the sensor exceeds a threshold minimum or maximum value or if the rate of change in the sensor signal exceeds a threshold value. In some cases, it may be necessary to wait a period of time after the implantation of the sensor before calibrating to allow the sensor to achieve equilibrium. In some embodiments, the sensor is calibrated only after it has been inserted. In other embodiments, no calibration of the sensor is needed. Exemplary calibration protocols are described, e.g., in U.S. Pat. No. 7,299,082, the disclosure of which is herein incorporated by reference.

Analyte Monitoring Device

In some embodiments, the present disclosure provides an analyte monitoring device which includes a sensor control unit such as, for example, the data processing unit2002 (FIG. 64) and an analyte sensor with an extruded electrode structure as described herein. In some embodiments, the processing circuit of the sensor control unit is able to determine a level of the analyte and activate an alarm system if the analyte level exceeds a threshold. The sensor control unit, in these embodiments, has an alarm system and may also include a display, such as an LCD or LED display. Alternatively, a similar alarm system may be provided in the receiver unit in signal communication with the sensor control unit.

A threshold value is exceeded if the datapoint has a value that is beyond the threshold value in a direction indicating a particular condition. For example, a datapoint which correlates to a glucose level of 200 mg/dL exceeds a threshold value for hyperglycemia of 180 mg/dL, because the datapoint indicates that the patient has entered a hyperglycemic state. As another example, a datapoint which correlates to a glucose level of 65 mg/dL exceeds a threshold value for hypoglycemia of 70 mg/dL because the datapoint indicates that the patient is hypoglycemic as defined by the threshold value. However, a datapoint which correlates to a glucose level of 75 mg/dL would not exceed the same threshold value for hypoglycemia because the datapoint does not indicate that particular condition as defined by the chosen threshold value.

An alarm may also be activated if the sensor readings indicate a value that is beyond a measurement range of the sensor. For glucose, the physiologically relevant measurement range is typically about 30 to 500 mg/dL, including about 40-300 mg/dL and about 50-250 mg/dL, of glucose in the interstitial fluid.

The alarm system may also, or alternatively, be activated when the rate of change or acceleration of the rate of change in analyte level increase or decrease reaches or exceeds a threshold rate or acceleration. For example, in the case of a subcutaneous glucose monitor, the alarm system might be activated if the rate of change in glucose concentration exceeds a threshold value which might indicate that a hyperglycemic or hypoglycemic condition is likely to occur.

A system may also include system alarms that notify a user of system information such as battery condition, calibration, sensor dislodgment, sensor malfunction, etc. Alarms may be, for example, auditory and/or visual. Other sensory-stimulating alarm systems may be used including alarm systems which heat, cool, vibrate, or produce a mild electrical shock when activated.

Dosage Calculation Function

In some embodiments, the analyte monitoring device is configured to perform medication dosage calculation functions, such as a single-dose calculation function for injection of rapid acting insulin and/or long acting insulin. Analyte meters which include medication dosage calculation functions and methods of performing the dosage calculation functions are described, for example, in U.S. patent application Ser. No. 11/396,182, filed Mar. 31, 2006, titled “Analyte Monitoring Devices and Methods Therefor,” the disclosure of which is incorporated by reference herein.

In one embodiment, the analyte monitoring device is configured to perform a bolus calculation function. For example, the analyte monitoring device may be configured to determine a bolus dosage, e.g., an insulin bolus dosage, based on the signal received from the analyte sensor.

Drug Delivery System

The present disclosure also provides sensor-based drug delivery systems utilizing the analyte sensors described herein. The system may provide a drug to counteract the high or low level of the analyte in response to the signals from one or more sensors. Alternatively, the system may monitor the drug concentration to ensure that the drug remains within a desired therapeutic range. The drug delivery system may include one or more (e.g., two or more) sensors, a processing unit such as a transmitter, a receiver/display unit, and a drug administration system. In some cases, some or all components may be integrated in a single unit. A sensor-based drug delivery system may use data from the one or more sensors to provide necessary input for a control algorithm/mechanism to adjust the administration of drugs, e.g., automatically or semi-automatically. As an example, a glucose sensor may be used to control and adjust the administration of insulin from an external or implanted insulin pump.

Additional information regarding integrated medication delivery devices or systems is provided, for example, in U.S. Patent Publication No. US2006/0224141, published on Oct. 5, 2006, titled “Method and System for Providing Integrated Medication Infusion and Analyte Monitoring System”, and U.S. Patent Publication No. US2004/0254434, published on Dec. 16, 2004, titled “Glucose Measuring Module and Insulin Pump Combination,” the disclosure of each of which is incorporated by reference herein.

Method of Making Extruded Electrode Structures and Analyte Sensors

The extruded electrode structures described herein can be prepared through the application of extrusion techniques which are well known in the art. In one embodiment, an electrode structure according to the present disclosure is produced by pushing or drawing heterogeneous material containing a dielectric material and one or more conductive materials, e.g., a dielectric polymer which includes one or more conductive stripes, through a die having a desired cross-section. In some embodiments, the material to be extruded can be heated prior to and/or during the extrusion process. Electrode structures having a first conductive material, a second conductive material, and a dielectric material can be coextruded in this manner to provide an electrode structure having the first conductive material and the second conductive material electrically isolated by the dielectric material.

A variety of shapes and sizes of electrode structures can be produced using these methods, including, but not limited to, those with solid, hollow, tubular, and/or rectangular box configurations as described previously herein. Extruded structures according to the present disclosure can be extruded individually (e.g.,FIG. 33) or alternatively an extruded electrode structure precursor can be produced which is then cut to the appropriate size to produce multiple electrode structures (e.g., an extruded electrode structure precursor as shown inFIG. 36 can be cut along the dashed lines indicated inFIG. 36 to produce two extruded electrode structures).

In some embodiments, subsequent to extrusion, the electrode structures are modified via skiving, drilling, cutting, laser processing, or other suitable method or combination thereof to expose one or more of the conductive materials. For example, one or more of these methods can be used to remove portions of the dielectric material so as to expose portions of one or both of the first conductive material and the second conductive material. Where an extruded electrode structure precursor is produced and then cut to produce multiple electrode structures, modification to expose one or more of the conductive materials can occur before, during, or after the precursor is cut to produce multiple electrode structures. Exposure of one or more of the conductive materials allows for deposition of sensing chemistry, e.g., to produce one or more working electrodes; or modification of the electrode structure for electrical connection with a connector, device, and/or additional electrode structure. An embodiment of a modified electrode structure which has been configured for electrical connection to a connector is shown, e.g., inFIGS. 40 and 41.

As an alternative to the deposition of sensing chemistry to produce one or more working electrodes, suitable sensing chemistry can be incorporated in, and extruded along with, one or more of the conductive materials, such that the coextruded structure contains one or more working electrodes without the need for subsequent sensing chemistry deposition. For example, sensing chemistry elements may be cross-linked to a conductive polymer, which, once extruded, provides an extruded working electrode.

In one embodiment, where an extruded electrode structure is to be configured as an analyte sensor, material used to configure a conductive material as a reference/counter electrode, e.g., Ag/AgCl, is incorporated in, and coextruded along with, the conductive material during production of the extruded electrode structure. This can help to avoid subsequent steps as it obviates any need to add reference/counter electrode material, e.g., Ag/AgCl, to the electrode structure subsequent to the extrusion process. For example, in one embodiment an extruded electrode structure includes an extruded conductive carbon stripe blended with Ag/AgCl.

One or more membranes may be applied over the sensing chemistry of the electrode structure, e.g., to create a diffusion-limiting barrier to reduce the rate of mass transport of the analyte, for example, glucose or lactate, into the region around the working electrode. An example of this process is depicted generally inFIG. 31. In some embodiments, the membrane may be deposited as a liquid, e.g., in a dropwise manner, which subsequently solidifies forming the membrane. In such embodiments, it may be desirable to further modify the membrane by removing excess membrane material to provide a uniform membrane surface. Excess membrane may also be removed to provide a membrane layer which is flush with the dielectric material of the electrode structure. Modification of the membrane as described above can reduce variation in the diffusion characteristics between different analyte sensors or batches of analyte sensors.

In some embodiments, one or more holes can be drilled through the electrode structure, e.g., to control the total uptake volume of fluid sample or expose indicator electrode contacts as described previously herein.

For certain applications, e.g., in vitro and in vivo analyte monitoring, it will be appropriate to sterilize the electrode structures following the extrusion process. Such sterilization can be accomplished using any suitable method known in the art.

Where an extruded electrode structure is configured for use as an in vivo analyte sensor, the extruded electrode structure can optionally have an anticlotting agent disposed on a portion of the sensor which is implanted into a patient. This anticlotting agent may reduce or eliminate the clotting of blood or other body fluid around the sensor, particularly after insertion of the sensor. Blood clots may foul the sensor or irreproducibly reduce the amount of analyte which diffuses into the sensor. Examples of useful anticlotting agents include heparin and tissue plasminogen activator (TPA), as well as other known anticlotting agents.

The anticlotting agent may be applied to at least a portion of that part of the sensor that is to be implanted. The anticlotting agent may be applied, for example, by bath, spraying, brushing, or dipping. The anticlotting agent is allowed to dry on the sensor. The anticlotting agent may be immobilized on the surface of the sensor or it may be allowed to diffuse away from the sensor surface. Typically, the quantities of anticlotting agent disposed on the sensor are far below the amounts typically used for treatment of medical conditions involving blood clots and, therefore, have only a limited, localized effect.

Insertion of Electrode Structures and Analyte Sensors

An insertion device can be used to subcutaneously insert the electrode structure or sensor into the patient. The insertion device is typically formed using structurally rigid materials, such as metal or rigid plastic. Exemplary materials include stainless steel and ABS (acrylonitrile-butadiene-styrene) plastic. In some embodiments, the insertion device is pointed and/or sharp at the tip to facilitate penetration of the skin of the patient. A sharp, thin insertion device may reduce pain felt by the patient upon insertion of the sensor. In other embodiments, the tip of the insertion device has other shapes, including a blunt or flat shape. These embodiments may be particularly useful when the insertion device does not penetrate the skin but rather serves as a structural support for the sensor as the sensor is pushed into the skin.

A variety of insertion devices and/or systems are known in the art, which can be modified for use with the extruded electrode structures and analyte sensors disclosed herein. In some embodiments, a standard infusion set used with insulin pumps may be utilized to facilitate insertion of an extruded electrode structure or analyte sensor as described herein. An additional insertion device and/or system which may be modified for use with the extruded electrode structures and analyte sensors described herein is the spring loaded insertion device used for the FreeStyle Navigator® continuous glucose monitoring system (available from Abbott Diabetes Care Inc.).

Additional information pertaining to insertion devices and/or systems and uses thereof can be found in U.S. Pat. Nos. 6,071,391; 6,103,033; 6,175,752; 6,329,161; 6,484,046; 6,560,471; 6,565,509, 6,973,706; 6,990,366; 7,003,340; 7,003,341; and 7,381,184, the disclosures of each of which are incorporated by reference herein.

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

Example 1Linearity Study Using Extruded Pebax® Working Electrode

A linearity study was conducted using an extruded Pebax® working electrode, a screen printed carbon counter electrode and a screen printed Ag/AgCl reference electrode. A testing station with LC-3D p-stats was used to test the electrodes. The extruded working electrode was paired through a potentiostat with the Ag/AgCl reference and carbon counter electrodes. Testing was carried out in 1000 ml PBS at 37° C. and AE=+40 mV. Glucose aliquots were added to produce concentrations of 1, 5, 10, and 20 mM, at various time points as evident from the humps inFIG. 67.

Two different sensing layers were utilized: A control sensing layer (PBX_C) 5% glucose oxidase sensing layer solution and a test sensing layer (PBX_M) 5% glucose oxidase sensing layer solution, 5% carbon nanopowder, 1% Triton X100. The respective sensing layers were deposited manually using a 0.5 μl syringe, 15 nL per working electrode. The two sensing layers were tested in groups of four replicates each.

A PVP membrane (poly(vinylpyridine), 130 mg/ml) was coated over the applied sensing layers by dipping the sensor tip into a membrane solution bath twice with a 10-minute interval and 5 mm/sec exit velocity. Extruded Pebax® tubing having a diameter of 0.012 inches and a resistance of ˜35 kΩ per inch was utilized in the preparation of the working electrodes.

The extruded electrode structures were exposed to varying glucose concentrations (0, 1, 5, 10, and 20 mM) at varying time points and current (nA) was measured using a 4.67 Mohm resistor.FIG. 67 shows a raw linearity chart (current nA vs. time), andFIG. 68 shows a linearity chart with current (nA) vs. glucose concentration in mM. The test sensors having 5% glucose oxidase sensing layer solution, 5% carbon nanopowder and 1% Triton X100 showed higher sensitivity (˜1.6 nA/mM) than the control sensors (˜0.23 nA/mM). It should be noted that one of the control sensors resulted in higher sensitivity due to fractures in the PVP membrane and was therefore excluded from the sensitivity measurement. The test sensors also showed faster response time than the control sensors.

These results demonstrate that an extruded electrode structure is capable of producing a sensitive and substantially linear response to changing glucose concentration. Furthermore, sensitivity was increased with the addition of 5% carbon nanopowder and 1% Triton X100 to the sensing layer.

Example 2Stability Study Using Extruded Pebax® Working Electrode

A stability study was conducted using an extruded Pebax® working electrode, a screen printed counter electrode and a screen printed Ag/AgCl reference electrode. Materials and methods were as described for Example 1, with the exception that the electrode structures were tested at a constant glucose concentration of 20 mM.FIG. 69 shows the results of the stability study. Less variation in the current (0.08% per hr) was seen for the control sensors relative to the test sensors. As with Example 1, data for the control sensor with fractures in the PVP membrane were excluded from the stability study. These results demonstrate that an extruded electrode structure is capable of producing a substantially stable response to glucose concentration.

Example 3Resistivity of Blended Conductive Polymer Materials

FIG. 70 provides a table which shows the results of resistivity measurements for three conductive polymer materials with different percentages of carbon blending. Pebax® polymer blended with 7, 10 or 13% carbon black were cut into small strips from casted plaques having a thickness of ˜1 mm. Strips were cut to the size of standard FreeStyle® test strips. Both ends of each strip were tightly inserted into a gold-plated female connector for stable connection. Resistance was measured across the connectors using a Fluke® multimeter. Using the measured resistance values, resistivity values were determined for each of the carbon-blended polymers.

Pebax® polymers having 7, 10, and 13% carbon black had mean resistivity values of 21.6, 6.3, and 4.9 respectively, with mean resistivity values of 6.3 and 4.9 falling within an acceptable range for electrodes. As such, Pebax® polymers having 10% and 13% carbon black had mean resistivity values indicating that these materials were suitable for use as electrodes.

Example 4Cyclic Voltammetry for Blended Conductive Polymer Materials

FIG. 71 compares cyclic voltammetric graphs of the conductive material used in FreeStyle® test strips (A05), Pebax® polymer blended with 7% carbon black (A03), and Pebax® polymer blended with 13% carbon black (A04).

Strips of the carbon-blended polymers were cut from casted plaques having a thickness of ˜1 mm. Strips were cut to the size of standard FreeStyle® test strips and tested in phosphate buffered saline (PBS) with standard individual counter and reference electrodes.

The results indicate that the electrochemical properties of the 13% carbon blended conductive polymer are similar to the carbon material used in currently available FreeStyle® test strips.

Example 5Resistivity and Extrusion Temperature Testing for Extruded Carbon-Blended Pebax® Polymers

In order to determine whether extruded conductive polymers would be suitable for use as electrodes, resistivity values for extruded carbon-blended polymer were determined. Strings of carbon-blended Pebax® polymer having 7, 10, and 13% carbon black were extruded on two different days. An extrusion temperature of 220±2° C. was used. Resistance was measured using a Fluke® multimeter and mean resistivity was calculated. The results of these experiments are provided below in Tables 1-6.

TABLE 1

Raw Material PEBAX (7% Carbon Black)
Extrusion Temp 220 ± 2°C.

					Mean
	#

1	#2	#3	#4	Resistivity

Diameter	0.0258	0.0233	0.0268	0.0226
(cm)
Length (cm)	284	291	223	351
Resistance	8.870	10.540	6.07	13.06
(MΩ)
Resistivity	16.35	15.41	15.33	14.95	15.51
(Ω · cm)

TABLE 2

Raw Material PEBAX (7% Carbon Black)
Extrusion Temp 220 ± 2°C.

						Mean
	#

1	#2	#3	#4	#5	Resistivity

Diameter	0.0516	0.0472	0.0510	0.0480	0.0518
(cm)
Length (cm)	48.5	27	92.5	70.5	57.5
Resistance	0.322	0.161	0.500	0.463	0.302
(MΩ)
Resistivity	13.87	10.45	11.04	11.89	11.05	11.66
(Ω · cm)

TABLE 3

Raw Material PEBAX (10% Carbon Black)
Extrusion Temp 220 ± 2°C.

					Mean
	#

1	#2	#3	#4	Resistivity

Diameter	0.0265	0.0265	0.0269	0.0274
(cm)
Length (cm)	233	217	303	288
Resistance	0.918	0.860	1.182	1.104
(MΩ)
Resistivity	2.17	2.19	2.22	2.25	2.21
(Ω · cm)

TABLE 4

Raw Material PEBAX (10% Carbon Black)
Extrusion Temp 220 ± 2°C.

						Mean
	#

1	#2	#3	#4	#5	Resistivity

Diameter	0.05	0.05	0.0513	0.0510	0.0477
(cm)
Length (cm)	85	93.5	73.5	94	63
Resistance	0.0832	0.093	0.0826	0.0916	0.0756
(MΩ)
Resistivity	1.92	1.94	2.32	1.99	2.15	2.06
(Ω · cm)

TABLE 5

Raw Material PEBAX (13% Carbon Black)
Extrusion Temp 220 ± 2°C.

				Mean
	#

1	#2	#3	Resistivity

Diameter (cm)	0.0206	0.0218	0.0223
Length (cm)	194	370	260
Resistance (MΩ)	2.395	4.302	3.232
Resistivity (Ω · cm)	4.12	4.36	4.86	4.45

TABLE 6

Raw Material PEBAX (13% Carbon Black)
Extrusion Temp 220 ± 2°C.

						Mean
	#

1	#2	#3	#4	#5	Resistivity

Diameter	0.0519	0.0522	0.0519	0.0510	0.0515
(cm)
Length (cm)	92	84	92	96	88
Resistance	0.189	0.168	0.193	0.1953	0.1857
(MΩ)
Resistivity	4.34	4.27	4.43	4.16	4.40	4.32
(Ω · cm)

The results shown in Tables 1-6 indicate that mean resistivity values for extruded carbon-blended Pebax® polymers having 10% and 13% carbon black are within an acceptable range for use as electrodes (e.g., less than 12 cm.Ω).

The effects of extrusion temperature variation on the resistivity of carbon-blended Pebax® polymers having 10% and 13% carbon black were also determined. The results of these experiments are provided below in Tables 7 and 8.

TABLE 7

					Extrusion
Sample	Carbon Black	Dimension (cm)	Resistance	Resistivity	Temp.	Mean

Name	Ratio (%)	Length	Diameter	(KΩ)	(Ω · cm)	(° F.)	(° C.)	Resistivity

10%	10	64	0.022	7580	45.0	280	138
Carbon	10	64.2	0.022	7640	45.2	280	138	39.9
Black	10	61.2	0.022	4737	29.4	265	129
10%	10	73.9	0.022	3041	15.6	295	146
Carbon	10	59.2	0.022	1818	11.7	308	153	13.0
Black	10	72	0.022	2199	11.6	308	153
10%	10	77.5	0.022	502.4	2.5	350	177
Carbon	10	85.7	0.022	564	2.5	350	177	2.5
Black	10	37.2	0.022	247.9	2.5	350	177
10%	10	62.8	0.022	374.3	2.3	450	232
Carbon	10	80.8	0.022	443.8	2.1	450	232	2.2
Black	10	51.6	0.022	301.6	2.2	450	232
	10	72.8	0.022	449.3	2.3	450	232

TABLE 8

	Carbon				Extrusion
Sample	Black	Dimension (cm)	Resistance	Resistivity	temperature	Mean

Name	Ratio (%)	Length	Diameter	(KΩ)	(Ω · cm)	(° F.)	(° C.)	Resistivity

13%	13	6.5	0.022	39630	2317.6	270	132
Carbon	13	5.2	0.022	38550	2818.1	260	127	1862.2
Black	13	14.6	0.022	41360	1076.9	280	138
	13	15.5	0.022	50410	1236.3	280	138
13%	13	63.3	0.022	52640	316.1	298	148
Carbon	13	35.3	0.022	33100	356.4	298	148	347.7
Black	13	48.7	0.022	47480	370.6	298	148
13%	13	65.5	0.022	1267	7.4	350	177
Carbon	13	65.5	0.022	1418	8.2	350	177	7.6
Black	13	55.8	0.022	1041	7.1	350	177
13%	13	25.3	0.025	184.3	3.6	450	232
Carbon	13	29.0	0.024	263.6	4.1	465	241	4.1
Black	13	61.5	0.024	622	4.6	465	241
	13	33.0	0.024	295.2	4.0	465	241

As indicated above in Tables 7 and 8, when extruded at relatively low temperatures (e.g., 127-148° C.) carbon-blended Pebax® polymers having 10% and 13% carbon black demonstrated mean resistivity values which exceeded those suitable for electrode use. However, higher extrusion temperatures (e.g., 177-241° C.) resulted in extruded conductive polymers having mean resistivity values in a suitable range for electrode use.

Example 6Resistivity Values for Extruded Carbon-Blended Pebax Polymer with Ag/AgCl

In order to determine the suitability for use in an electrode structure of an extruded conductive polymer having a blend of carbon black and Ag/AgCl, pellets of 10% carbon-blended Pebax® coated with Ag/AgCl ink were melted and extruded as a polymer string. The resulting extruded structure had a diameter of 0.05 cm and a length of 17.5 cm. When tested, the extruded conductive polymer had a resistance of 0.015 MΩ, and a determined resistivity of 1.67 Ω·cm. These results indicate that an extruded conductive polymer which includes a blend of carbon black and Ag/AgCl has resistivity characteristics making it suitable for use in an electrode structure.

Example 7Resistance Measurements for Extruded Conductive Polymer Tubing

In order to determine resistance characteristics for extruded conductive tubing, Pebax® polymer was coextruded with 10% carbon-blended Pebax® polymer to produce a 0.88 mm diameter tube structure having two conductive stripes of 10% carbon-blended Pebax® positioned in the walls of the tube and electrically isolated from each other by the co-extruded Pebax® polymer. The conductive tubing was extruded such that the two conductive stripes extended the length of the tubing. Resistance was measured for each of the conductive stripes of the tubing. The results of these measurements are provided below in Table 9.

TABLE 9

				Unit				Unit
		Length
1	Resistance	Resistance		Length	2	Resistance	Resistance
ID	Color 1	(mm)	1 (kΩ)	(kΩ/mm)	Color 2	(mm)	2 (kΩ)	(kΩ/mm)

A1	black	27	71.1	2.63	red	31	71.3	2.30
A2	yellow	25	35.5	1.42	red	29	56.7	1.96
A3	yellow	26	45.65	1.76	red	30	59.8	1.99
A4	black	28	57.4	2.05	red	32	114.3	3.57

For each of the four extruded structures tested, each of the conductive stripes demonstrated a resistance value in a suitable range for use as an electrode, e.g., less than 40 kΩ/mm.

The preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.